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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Scope The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology, and educational items in the various related topics for students in Medicine and in Sciences. Editorial correspondance Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected] Staff Mohammad Ahmad, Mélanie Arsaban, Houa Delabrousse, Marie-Christine Jacquemot-Perbal, Maureen Labarussias, Vanessa Le Berre, Anne Malo, Catherine Morel-Pair, Laurent Rassinoux, Sylvie Yau Chun Wan - Senon, Alain Zasadzinski. Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France). The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French National Center for Scientific Research (INIST-CNRS) since 2008. The Atlas is hosted by INIST-CNRS (http://www.inist.fr) http://AtlasGeneticsOncology.org © ATLAS - ISSN 1768-3262 The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS. Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Editor Jean-Loup Huret (Poitiers, France) Editorial Board Sreeparna Banerjee Alessandro Beghini Anne von Bergh Judith Bovée Vasantha Brito-Babapulle Charles Buys Anne Marie Capodano Fei Chen Antonio Cuneo Paola Dal Cin Louis Dallaire Brigitte Debuire François Desangles Enric Domingo-Villanueva Ayse Erson Richard Gatti Ad Geurts van Kessel Oskar Haas Anne Hagemeijer Nyla Heerema Jim Heighway Sakari Knuutila Lidia Larizza Lisa Lee-Jones Edmond Ma Roderick McLeod Cristina Mecucci Yasmin Mehraein Fredrik Mertens Konstantin Miller Felix Mitelman Hossain Mossafa Stefan Nagel Florence Pedeutour Elizabeth Petty Susana Raimondi Mariano Rocchi Alain Sarasin Albert Schinzel Clelia Storlazzi Sabine Strehl Nancy Uhrhammer Dan Van Dyke Roberta Vanni Franck Viguié José Luis Vizmanos Thomas Wan (Ankara, Turkey) (Milan, Italy) (Rotterdam, The Netherlands) (Leiden, The Netherlands) (London, UK) (Groningen, The Netherlands) (Marseille, France) (Morgantown, West Virginia) (Ferrara, Italy) (Boston, Massachussetts) (Montreal, Canada) (Villejuif, France) (Paris, France) (London, UK) (Ankara, Turkey) (Los Angeles, California) (Nijmegen, The Netherlands) (Vienna, Austria) (Leuven, Belgium) (Colombus, Ohio) (Liverpool, UK) (Helsinki, Finland) (Milano, Italy) (Newcastle, UK) (Hong Kong, China) (Braunschweig, Germany) (Perugia, Italy) (Homburg, Germany) (Lund, Sweden) (Hannover, Germany) (Lund, Sweden) (Cergy Pontoise, France) (Braunschweig, Germany) (Nice, France) (Ann Harbor, Michigan) (Memphis, Tennesse) (Bari, Italy) (Villejuif, France) (Schwerzenbach, Switzerland) (Bari, Italy) (Vienna, Austria) (Clermont Ferrand, France) (Rochester, Minnesota) (Montserrato, Italy) (Paris, France) (Pamplona, Spain) (Hong Kong, China) Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Solid Tumours Section Genes Section Genes / Leukaemia Sections Solid Tumours Section Leukaemia Section Deep Insights Section Solid Tumours Section Genes / Deep Insights Sections Leukaemia Section Genes / Solid Tumours Section Education Section Deep Insights Section Leukaemia / Solid Tumours Sections Solid Tumours Section Solid Tumours Section Cancer-Prone Diseases / Deep Insights Sections Cancer-Prone Diseases Section Genes / Leukaemia Sections Deep Insights Section Leukaemia Section Genes / Deep Insights Sections Deep Insights Section Solid Tumours Section Solid Tumours Section Leukaemia Section Deep Insights / Education Sections Genes / Leukaemia Sections Cancer-Prone Diseases Section Solid Tumours Section Education Section Deep Insights Section Leukaemia Section Deep Insights / Education Sections Genes / Solid Tumours Sections Deep Insights Section Genes / Leukaemia Section Genes Section Cancer-Prone Diseases Section Education Section Genes Section Genes / Leukaemia Sections Genes / Cancer-Prone Diseases Sections Education Section Solid Tumours Section Leukaemia Section Leukaemia Section Genes / Leukaemia Sections Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Volume 14, Number 12, December 2010 Table of contents Gene Section CKS2 (CDC28 protein kinase regulatory subunit 2) Yongyou Zhang 1100 CRTC2 (CREB regulated transcription coactivator 2) Kristy A Brown, Nirukshi Samarageewa 1104 IL22RA1 (interleukin 22 receptor, alpha 1) Pascal Gelebart, Raymond Lai 1106 MAPK7 (mitogen-activated protein kinase 7) Francisco de Asís Iñesta-Vaquera, Ana Cuenda 1111 SLC16A1 (solute carrier family 16, member 1 (monocarboxylic acid transporter 1)) Céline Pinheiro, Fátima Baltazar 1115 STOML2 (stomatin (EPB72)-like 2) Wenfeng Cao, Liyong Zhang, Fang Ding, Zhumei Cui, Zhihua Liu 1118 AMOT (angiomotin) Roshan Mandrawalia, Ranjan Tamuli 1121 BRCA2 (breast cancer 2, early onset) Frédéric Guénard, Francine Durocher 1124 FST (follistatin) Michael Grusch 1132 GATA6 (GATA binding protein 6) Rosalyn M Adam, Joshua R Mauney 1136 HIPK2 (homeodomain interacting protein kinase 2) Dirk Sombroek, Thomas G Hofmann 1141 RAD9A (RAD9 homolog A (S. pombe)) Vivian Chan 1145 SCAF1 (SR-related CTD-associated factor 1) Christos Kontos, Andreas Scorilas 1149 SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)) Ruo-Chia Tseng, Yi-Ching Wang 1152 SLC16A3 (solute carrier family 16, member 3 (monocarboxylic acid transporter 4)) Céline Pinheiro, Fátima Baltazar 1157 SPAM1 (sperm adhesion molecule 1 (PH-20 hyaluronidase, zona pellucida binding)) Asli Sade, Sreeparna Banerjee 1160 TMPRSS2 (transmembrane protease, serine 2) Youngwoo Park 1163 TMSB10 (thymosin beta 10) Xueshan Qiu 1166 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) t(11;14)(q13;q32) in multiple myeloma Atlas of Genetics and Cytogenetics in Oncology and Haematology Huret JL, Laï JL OPEN ACCESS JOURNAL AT INIST-CNRS TYMP (thymidine phosphorylase) Irene V Bijnsdorp, Godefridus J Peters 1170 Leukaemia Section der(6)t(1;6)(q21-23;p21) Adriana Zamecnikova 1175 ins(9;4)(q33;q12q25) Jean-Loup Huret 1177 Solid Tumour Section t(19;22)(q13;q12) in myoepithelial carcinoma Jean-Loup Huret 1179 Deep Insight Section Glutathione S-Transferase pi (GSTP1) Isabelle Meiers 1181 The roles of SRA1 gene in breast cancer Yi Yan, Charlton Cooper, Etienne Leygue 1186 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review CKS2 (CDC28 protein kinase regulatory subunit 2) Yongyou Zhang Case Western Reserve University, WRB-3101, 2103 Cornell Rd, Cleveland, OH 44106, USA (YZ) Published in Atlas Database: February 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/CKS2ID40093ch9q22.html DOI: 10.4267/2042/44906 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Description Identity The open reading frame encodes a 79 amino acid protein, with an estimated molecular weight of approximately 9860 Da. Other names: CKSHS2 HGNC (Hugo): CKS2 Location: 9q22.2 Note: There is no evidence that CKS2 gene has different transcript variant. Expression Basic level expression in all mammalian cells and aberrant expression in cancer cells. Localisation DNA/RNA Cytoplasm and nucleus. Function Transcription CKS2 protein binds to the catalytic subunit of the cyclin-dependent kinases and is essential for their biological function of cell cycle control. Especially, CKS2 is required for the first metaphase/anaphase transition of mammalian meiosis. The mice ablated of Cks2 are viable but sterile in both sexes. Sterility is due to failure of both male and female germ cells to progress from the first meiotic metaphase to anaphase. In cancer cells, CKS2 may protect the cells from apoptosis. mRNA is 627 bp. Homology Pseudogene The CKS2 protein is evolutionary conserved. Mammalian cells express two well-conserved CKS members, like the human CKS2 and CKS1B proteins. CKS2 and CKS1B may have redundant function in some context and have different functions in other context. The CKS2 protein is highly conserved cross species. Genomic organization of the CKS2 gene. Description Three exons, spans approximately 5.5 kb of genomic DNA in the centromere-to-telomere orientation. The translation initiation codon ATG is located in exon 1, and the stop codon in exon 3. 1 processed, non-expressed, pseudogene in human genome. Protein Note The Cks2 protein can form a special homohexamer structure. Six kinase subunits can bind the assembled hexamer, and therefore this Cks2 hexamer may participate in cell cycle control by acting as the hub for Cdk multimerization in vivo. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Mutations Note Mutation of glutamine for glutamate 63 (E63Q), 1100 CKS2 (CDC28 protein kinase regulatory subunit 2) Zhang Y disrupted the essential biological function of the protein and significantly reduced its ability to bind to cyclindependent kinases, but preserves protein structure and assembly. (Wiese et al., 2007). CKS2 was also showed to be higher in liver metastasis compared with primary colon cancer (Lin et al., 2007). Oncogenesis Amplification and overexpression of CKS2 were associated with liver metastasis and poor prognosis in colon cancer. CKS2 is required for germ cell to go past the first meiotic metaphase and enter anaphase. In cancer cell, overexpression of CKS2 can accelerate the cell cycles and promote the cell proliferation. Recently research showed that CKS2 may also be involved in apoptosis and metabolism since it can protect mitochondrial genome integrity via interaction with mitochondrial single-stranded DNA-binding protein. Study also showed CKS2 as a transcriptional target downregulated by the tumor suppressor p53. CKS2 expression was found to be repressed by p53 both at the mRNA and the protein levels, which may provide a mechanism that explain why CKS2 is upregulated in many types of cancer. All of these suggest that CKS2 alterations may have a significant biological role in the tumorigenesis in different tissue. The novel therapeutic strategy for cancer though may be developed via inhibiting the CKS2 activity. Therefore, disruption of CKS2-Cyclin Complex assembly or down-regulation of CKS2 expression may be used for cancer therapy. Implicated in Various cancers Note Emerging evidence showed that the expression of CKS2 is elevated in multiple cancers, including prostate cancer, breast cancer, gastric cancer, colorectal cancer, uterine cervical cancer, bladder cancer, nasopharyngeal carcinoma, melanoma, lymphoma, lung cancer, esophageal squamous cell carcinoma et al. The expression of CKS2 is correlated with poor survival rate of the patients of some cancers. Prognosis Overexpression of CKS2 has been reported to be associated with high aggressiveness and a poor prognosis in multiple cancers, including breast cancer, prostate cancer, colon cancer, hepatocellular carcinoma and meningiomas et al. Hepatocellular carcinoma (HCC) Note Expressions of CKS2 were significantly higher in HCC compared with the adjacent noncancerous tissues (including chronic hepatitis and cirrhosis) and normal liver tissues. Overexpression of CKS2 in HCC were closely associated with poor differentiation features (Shen et al., 2010). Esophageal squamous cell carcinoma Note Gene expression profiling of lymph node metastasis by oligomicroarray analysis and Real-time RT-PCR confirmed that CKS2 is unregulated in laser microdissection of esophageal squamous cell carcinoma compared with adjacent normal tissue (Uchikado et al., 2006). Gastric cancer Note CKS2 was showed to be significantly unregulated in gastric cancers. The high level of CKS2 was highly correlated with tumor differentiation and pathological grade of the tumor size, lymph node, and metastasis stage (Kang et al., 2009). Uterine cervical cancer Note CKS2 was showed significantly higher in node positive tumor compared with negative one. The CKS2 expression is correlated with metastatic phenotypes and progression free survival. (Lyng et al., 2006). Prostate cancer Note CKS2 were significantly unregulated in prostate tumors of human and animal models, as well as prostatic cancer cell lines. Forced expression of CKS2 in benign prostate tumor epithelial cells promoted cell population growth. Inhibition of CKS2 expression can induce programmed cell death and inhibit the tumorigenesis. (Lan et al., 2008). Over expression of CKS2 may linked with androgen-independent prostate cancer progression (Stanbrough et al., 2006). Bladder cancer Note Large-scale gene expression profiling and Real-Time RT-PCR confirmed that a the CKS2 expression is elevated in invasive bladder cancer compared with superficial cancer (Kawakami et al., 2006). Glioblastoma Note CKS2 was significantly up-regulated in primary glioblastomas compared with the non-neoplastic brain tissues (Scrideli et al., 2008). Colon cancer Note CKS2 was reported significantly overexpressed in microdissected invasive colon tumor cells compared with adjacent normal epithelial cells Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Meningioma Note This microarray-based expression profiling study 1101 CKS2 (CDC28 protein kinase regulatory subunit 2) Zhang Y bladder cancer through genome-wide gene profiling. Oncol Rep. 2006 Sep;16(3):521-31 showed CKS2 is unregulated in atypical and anaplastic meningiomas compared with benign meningiomas (Fevre-Montange et al., 2009). Lyng H, Brøvig RS, Svendsrud DH, Holm R, Kaalhus O, Knutstad K, Oksefjell H, Sundfør K, Kristensen GB, Stokke T. Gene expressions and copy numbers associated with metastatic phenotypes of uterine cervical cancer. BMC Genomics. 2006 Oct 20;7:268 References Parge HE, Arvai AS, Murtari DJ, Reed SI, Tainer JA. Human CksHs2 atomic structure: a role for its hexameric assembly in cell cycle control. Science. 1993 Oct 15;262(5132):387-95 Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, Febbo PG, Balk SP. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006 Mar 1;66(5):2815-25 Demetrick DJ, Zhang H, Beach DH. Chromosomal mapping of the human genes CKS1 to 8q21 and CKS2 to 9q22. Cytogenet Cell Genet. 1996;73(3):250-4 Uchikado Y, Inoue H, Haraguchi N, Mimori K, Natsugoe S, Okumura H, Aikou T, Mori M. Gene expression profiling of lymph node metastasis by oligomicroarray analysis using laser microdissection in esophageal squamous cell carcinoma. Int J Oncol. 2006 Dec;29(6):1337-47 Pines J. Cell cycle: reaching for a role for the Cks proteins. Curr Biol. 1996 Nov 1;6(11):1399-402 Watson MH, Bourne Y, Arvai AS, Hickey MJ, Santiago A, Bernstein SL, Tainer JA, Reed SI. A mutation in the human cyclin-dependent kinase interacting protein, CksHs2, interferes with cyclin-dependent kinase binding and biological function, but preserves protein structure and assembly. J Mol Biol. 1996 Sep 6;261(5):646-57 Wong YF, Cheung TH, Tsao GS, Lo KW, Yim SF, Wang VW, Heung MM, Chan SC, Chan LK, Ho TW, Wong KW, Li C, Guo Y, Chung TK, Smith DI. Genome-wide gene expression profiling of cervical cancer in Hong Kong women by oligonucleotide microarray. Int J Cancer. 2006 May 15;118(10):2461-9 Egan EA, Solomon MJ. Cyclin-stimulated binding of Cks proteins to cyclin-dependent kinases. Mol Cell Biol. 1998 Jul;18(7):3659-67 Lin CY, Ström A, Li Kong S, Kietz S, Thomsen JS, Tee JB, Vega VB, Miller LD, Smeds J, Bergh J, Gustafsson JA, Liu ET. Inhibitory effects of estrogen receptor beta on specific hormone-responsive gene expression and association with disease outcome in primary breast cancer. Breast Cancer Res. 2007;9(2):R25 Urbanowicz-Kachnowicz I, Baghdassarian N, Nakache C, Gracia D, Mekki Y, Bryon PA, Ffrench M. ckshs expression is linked to cell proliferation in normal and malignant human lymphoid cells. Int J Cancer. 1999 Jul 2;82(1):98-104 Seeliger MA, Schymkowitz JW, Rousseau F, Wilkinson HR, Itzhaki LS. Folding and association of the human cell cycle regulatory proteins ckshs1 and ckshs2. Biochemistry. 2002 Jan 29;41(4):1202-10 Lin HM, Chatterjee A, Lin YH, Anjomshoaa A, Fukuzawa R, McCall JL, Reeve AE. Genome wide expression profiling identifies genes associated with colorectal liver metastasis. Oncol Rep. 2007 Jun;17(6):1541-9 Donovan PJ, Reed SI. Germline exclusion of Cks1 in the mouse reveals a metaphase I role for Cks proteins in male and female meiosis. Cell Cycle. 2003 Jul-Aug;2(4):275-6 Rother K, Dengl M, Lorenz J, Tschöp K, Kirschner R, Mössner J, Engeland K. Gene expression of cyclin-dependent kinase subunit Cks2 is repressed by the tumor suppressor p53 but not by the related proteins p63 or p73. FEBS Lett. 2007 Mar 20;581(6):1166-72 Lu X, Guo J, Hsieh TC. PC-SPES inhibits cell proliferation by modulating p21, cyclins D, E and B and multiple cell cyclerelated genes in prostate cancer cells. Cell Cycle. 2003 JanFeb;2(1):59-63 Wiese AH, Auer J, Lassmann S, Nährig J, Rosenberg R, Höfler H, Rüger R, Werner M. Identification of gene signatures for invasive colorectal tumor cells. Cancer Detect Prev. 2007;31(4):282-95 Seeliger MA, Breward SE, Itzhaki LS. Weak cooperativity in the core causes a switch in folding mechanism between two proteins of the cks family. J Mol Biol. 2003 Jan 3;325(1):189-99 Haaber J, Abildgaard N, Knudsen LM, Dahl IM, Lodahl M, Thomassen M, Kerndrup GB, Rasmussen T. Myeloma cell expression of 10 candidate genes for osteolytic bone disease. Only overexpression of DKK1 correlates with clinical bone involvement at diagnosis. Br J Haematol. 2008 Jan;140(1):2535 Spruck CH, de Miguel MP, Smith AP, Ryan A, Stein P, Schultz RM, Lincoln AJ, Donovan PJ, Reed SI. Requirement of Cks2 for the first metaphase/anaphase transition of mammalian meiosis. Science. 2003 Apr 25;300(5619):647-50 Li M, Lin YM, Hasegawa S, Shimokawa T, Murata K, Kameyama M, Ishikawa O, Katagiri T, Tsunoda T, Nakamura Y, Furukawa Y. Genes associated with liver metastasis of colon cancer, identified by genome-wide cDNA microarray. Int J Oncol. 2004 Feb;24(2):305-12 Lan Y, Zhang Y, Wang J, Lin C, Ittmann MM, Wang F. Aberrant expression of Cks1 and Cks2 contributes to prostate tumorigenesis by promoting proliferation and inhibiting programmed cell death. Int J Cancer. 2008 Aug 1;123(3):54351 de Wit NJ, Rijntjes J, Diepstra JH, van Kuppevelt TH, Weidle UH, Ruiter DJ, van Muijen GN. Analysis of differential gene expression in human melanocytic tumour lesions by custom made oligonucleotide arrays. Br J Cancer. 2005 Jun 20;92(12):2249-61 Martinsson-Ahlzén HS, Liberal V, Grünenfelder B, Chaves SR, Spruck CH, Reed SI. Cyclin-dependent kinase-associated proteins Cks1 and Cks2 are essential during early embryogenesis and for cell cycle progression in somatic cells. Mol Cell Biol. 2008 Sep;28(18):5698-709 Chow LS, Lam CW, Chan SY, Tsao SW, To KF, Tong SF, Hung WK, Dammann R, Huang DP, Lo KW. Identification of RASSF1A modulated genes in nasopharyngeal carcinoma. Oncogene. 2006 Jan 12;25(2):310-6 Scrideli CA, Carlotti CG Jr, Okamoto OK, Andrade VS, Cortez MA, Motta FJ, Lucio-Eterovic AK, Neder L, Rosemberg S, Oba-Shinjo SM, Marie SK, Tone LG. Gene expression profile analysis of primary glioblastomas and non-neoplastic brain tissue: identification of potential target genes by oligonucleotide microarray and real-time quantitative PCR. J Neurooncol. 2008 Jul;88(3):281-91 Kawakami K, Enokida H, Tachiwada T, Gotanda T, Tsuneyoshi K, Kubo H, Nishiyama K, Takiguchi M, Nakagawa M, Seki N. Identification of differentially expressed genes in human Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) expression 1102 CKS2 (CDC28 protein kinase regulatory subunit 2) Zhang Y Fèvre-Montange M, Champier J, Durand A, Wierinckx A, Honnorat J, Guyotat J, Jouvet A. Microarray gene expression profiling in meningiomas: differential expression according to grade or histopathological subtype. Int J Oncol. 2009 Dec;35(6):1395-407 treatment in breast cancer. J Steroid Biochem Mol Biol. 2010 Feb 28;118(4-5):273-6 Radulovic M, Crane E, Crawford M, Godovac-Zimmermann J, Yu VP. CKS proteins protect mitochondrial genome integrity by interacting with mitochondrial single-stranded DNA-binding protein. Mol Cell Proteomics. 2010 Jan;9(1):145-52 Kang MA, Kim JT, Kim JH, Kim SY, Kim YH, Yeom YI, Lee Y, Lee HG. Upregulation of the cycline kinase subunit CKS2 increases cell proliferation rate in gastric cancer. J Cancer Res Clin Oncol. 2009 Jun;135(6):761-9 Shen DY, Fang ZX, You P, Liu PG, Wang F, Huang CL, Yao XB, Chen ZX, Zhang ZY. Clinical significance and expression of cyclin kinase subunits 1 and 2 in hepatocellular carcinoma. Liver Int. 2010 Jan;30(1):119-25 Wang F, Kuang Y, Salem N, Anderson PW, Lee Z. Crossspecies hybridization of woodchuck hepatitis viral infectioninduced woodchuck hepatocellular carcinoma using human, rat and mouse oligonucleotide microarrays. J Gastroenterol Hepatol. 2009 Apr;24(4):605-17 This article should be referenced as such: Zhang Y. CKS2 (CDC28 protein kinase regulatory subunit 2). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):11001103. Miller WR. Clinical, pathological, proliferative and molecular responses associated with neoadjuvant aromatase inhibitor Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1103 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review CRTC2 (CREB regulated transcription coactivator 2) Kristy A Brown, Nirukshi Samarageewa Prince Henry's Institute, Clayton, Victoria, 3168, Australia (KAB, NS) Published in Atlas Database: February 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/CRTC2ID50581ch1q21.html DOI: 10.4267/2042/44907 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology localisation sequence (NLS) at amino acids 56-144 as well as two nuclear export sequences (NES1 and NES2) within the region of amino acids 145-320. Identity Other names: TORC2, RP11-422P24.6 HGNC (Hugo): CRTC2 Location: 1q21.3 Function Transcriptional coactivator for CREB (cAMPresponsive element binding protein).The highly conserved N-terminal coiled-coil domain of the CRTC2 interacts with the bZip domain of CREB which activates both consensus and variant cAMP response element (CRE) sites, leading to activation of CREB target gene expression. CRTC2 responds to stimulation by cAMP, calcium, fasting hormones, G proteincoupled receptors, and AMPK/SIKs. DNA/RNA Description 10,893 bases; on minus strand. Includes 14 exons. Transcription Transcript measures 2598 bp with a 2082 bp coding sequence. Implicated in Protein Peutz-Jeghers syndrome Description Note Peutz-Jeghers syndrome (PJS) is an autosomaldominant genetic disorder that is characterised by an increased risk of developing malignant tumours. Most of the identified mutations in the LKB1 gene are localised to the catalytic kinase domain so that it is thought that PJS results from loss of LKB1 kinase activity. The silencing of LKB1, leads to the decreased activity of AMPK and SIK and leads to the increased nuclear translocation and activity of CRTC2. Disease Gastrointestinal polyps and cancers including esophagus, stomach, small intestine, colon, pancreas, lung, testes, breast, uterus, ovary and cervix. 693 amino acids; 73,302 Da. Expression Particularly abundant in B and T lymphocytes. Higher levels were also seen in muscle, lung, spleen, ovary and breast. Lower expressions found in brain, colon, heart, kidney, prostate, small intestine and stomach, with significantly lowest expression in liver and pancreas. Localisation Phosphorylation of CRTC2 triggers the phosphorylation-dependent binding to 14-3-3 proteins, and hence sequestration of CRTC2 in the cytosol thereby preventing its nuclear translocation and the activation of CREB. Proteins known to phosphorylate CRTC2 at Ser171 include AMP- Oestrogen-receptor (ER) positive breast cancer Note The increased prevalence of oestrogen-dependent, postmenopausal breast cancers is correlated with activated protein kinase (AMPK) and the salt-inducible kinases (SIKs). Dephosphorylated CRTC2 readily translocates to the nucleus. CRTC2 contains a nuclear Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1104 CRTC2 (CREB regulated transcription coactivator 2) Brown KA, Samarageewa N Okamoto M, Montminy M. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell. 2004 Oct 1;119(1):61-74 elevated local levels of oestrogens as a result of an increase in cytochrome P450 aromatase expression within the adipose stromal (hAS) cells surrounding the breast tumour - aromatase is the enzyme responsible for the conversion of androgens to oestrogens. This is governed by promoter switching from the distal promoter I.4 to the proximal promoter PII on the CYP19A1 gene, that encodes aromatase, in response to factors derived from the tumour such as prostaglandin E2 (PGE2). Interestingly, the LKB1/ AMPK pathway has been shown to inhibit aromatase expression via the cytoplasmic sequestration of CRTC2. However, PGE2 inhibits LKB1/AMPK signaling, leading to the nuclear translocation of CRTC2 and its enhanced binding and activation of aromatase promoter PII in hAS cells. Furthermore, the adipokine leptin, produced at higher levels in obesity, has been shown to cause an increase in CRTC2 nuclear translocation and consequently, in aromatase expression. Alessi DR, Sakamoto K, Bayascas JR. LKB1-dependent signaling pathways. Annu Rev Biochem. 2006;75:137-63 Katoh Y, Takemori H, Lin XZ, Tamura M, Muraoka M, Satoh T, Tsuchiya Y, Min L, Doi J, Miyauchi A, Witters LA, Nakamura H, Okamoto M. Silencing the constitutive active transcription factor CREB by the LKB1-SIK signaling cascade. FEBS J. 2006 Jun;273(12):2730-48 Shaw RJ. Glucose metabolism and cancer. Curr Opin Cell Biol. 2006 Dec;18(6):598-608 Wu Z, Huang X, Feng Y, Handschin C, Feng Y, Gullicksen PS, Bare O, Labow M, Spiegelman B, Stevenson SC. Transducer of regulated CREB-binding proteins (TORCs) induce PGC1alpha transcription and mitochondrial biogenesis in muscle cells. Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):1437984 Brown KA, McInnes KJ, Hunger NI, Oakhill JS, Steinberg GR, Simpson ER. Subcellular localization of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 provides a link between obesity and breast cancer in postmenopausal women. Cancer Res. 2009 Jul 1;69(13):53929 References Conkright MD, Canettieri G, Screaton R, Guzman E, Miraglia L, Hogenesch JB, Montminy M. TORCs: transducers of regulated CREB activity. Mol Cell. 2003 Aug;12(2):413-23 Brown KA, Simpson ER. Obesity and breast cancer: progress to understanding the relationship. Cancer Res. 2010 Jan 1;70(1):4-7 Sofi M, Young MJ, Papamakarios T, Simpson ER, Clyne CD. Role of CRE-binding protein (CREB) in aromatase expression in breast adipose. Breast Cancer Res Treat. 2003 Jun;79(3):399-407 This article should be referenced as such: Brown KA, Samarageewa N. CRTC2 (CREB regulated transcription coactivator 2). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1104-1105. Screaton RA, Conkright MD, Katoh Y, Best JL, Canettieri G, Jeffries S, Guzman E, Niessen S, Yates JR 3rd, Takemori H, Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1105 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review IL22RA1 (interleukin 22 receptor, alpha 1) Pascal Gelebart, Raymond Lai Department of Laboratory Medicine and Pathology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada (PG, RL) Published in Atlas Database: February 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/IL22RA1ID44568ch1p36.html DOI: 10.4267/2042/44908 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity nucleotides, encoding a protein of 594 amino acid residues. Other names: CRF2-9, IL22R, IL22R1 HGNC (Hugo): IL22RA1 Location: 1p36.11 Pseudogene None. Protein DNA/RNA Description Description IL22RA1 is composed of 574 amino acid residues, and the predicted molecular weight of the immature protein is 63 kDa. IL22RA1 protein is composed of six putative domains, including the signal peptide (residue 1 to 15), the extracellular domain (residue 16 to 228), the transmembrane domain (residue 229 to 249), the cytoplasmic domain (residue 250 to 574), and two fibronectin type-III domains (residue 18-115 and 141221). The gene spans a region of 23.3 kb including seven exons. Transcription One only transcript form containing 7 exons has been described. The last exon is partially untranslated. The transcript length is 1725 Representation of the IL22RA1 gene organization. IL22RA1 gene and RNA. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1106 IL22RA1 (interleukin 22 receptor, alpha 1) Gelebart P, Lai R IL22RA1 protein organization and localization. IL22RA1 protein domains. Localization of IL22RA1 by immunufluorescence confocal microscopy in ALK+ALCL cells. Expression IL22RA1 expression is relatively restricted, being found at the highest level in the pancreas, small intestine, colon, kidney, and liver. Importantly, IL22RA1 is not detectable in normal immune cells, including monocytes, B-cells, T-cells, natural killer cells, macrophages and dendritic cells, cell types that are normally found in the bone marrow, peripheral blood, thymus and spleen. Localisation IL22RA1 is localized at the plasma membrane. Crystal structure of IL22RA1 with IL22 at 1.9 A resolution. Adapted from PDB (access number: 3DLQ). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1107 IL22RA1 (interleukin 22 receptor, alpha 1) Gelebart P, Lai R FACS analysis of IL22RA1 expression in peripheral mononuclear cells from healthy donor. IL22RA1 signaling. and translocate to the nucleus to modulate the transcription of various target genes. Function IL22RA1 is one of the subunits of the IL20, IL22 and IL24 receptor complex. Cytokine binding to IL22RA1 results in its aggregation, which activates the associated JAK via its autophosphorylation. This in turn leads to the phosphorylation and activation of STAT proteins. Subsequently, phosphorylated STAT proteins dimerize Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Mutations Site-directed mutagenesis experiments have revealed critical amino acid residues involved in its binding to IL22. Specifically, mutation of residue 58 from K to A 1108 IL22RA1 (interleukin 22 receptor, alpha 1) Gelebart P, Lai R reduces the binding of IL22. Mutation of the residue 60 from Y to A or R results in a complete loss of response to IL22. Natural IL22RA1 variants have been reported, including those carrying mutations at the residue 130 (S to P), 205 (V to I), 209 (A to S), 222 (L to P), 407 (M to V) and 518 (R to G). the chromosomal translocation is that of the t(2;5)(p23;q35), which leads to the juxtaposition of the nucleophosmin (NPM) gene at 5q35 with the ALK gene at 2p23. Mounting evidence suggests that the resulted oncogenic fusion protein, NPM-ALK, plays crucial roles in the pathogenesis of these tumors. Prognosis Patients with ALK+ALCL are typically treated with combination chemotherapy containing doxorubicin. ALK+ALCL represents one of the most common pediatric lymphoid malignancies. The prognosis of pediatric ALK+ALCL patients is significant better than that of adult patients. Cytogenetics t(2;5)(p23;q35) in most ALK+ALCL patients; other translocation variants have been described. Hybrid/Mutated gene NPM-ALK Implicated in ALK-positive anaplastic large cell lymphoma (ALK+ALCL) Disease Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL), or ALK+ALCL, is a specific type of non-Hodgkin lymphoma characterized by the T/null-cell immunophenotype, consistent expression of CD30 and reciprocal chromosomal translocations involving the ALK gene. In most cases, Representation of the NPM-ALK oncoprotein organization and sequence. Abnormal protein NPM-ALK References Kotenko SV, Izotova LS, Mirochnitchenko OV, Esterova E, Dickensheets H, Donnelly RP, Pestka S. Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta ) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes. J Biol Chem. 2001 Jan 26;276(4):2725-32 Structure of the oncogenic fusion protein NPM-ALK. Lécart S, Morel F, Noraz N, Pène J, Garcia M, Boniface K, Lecron JC, Yssel H. IL-22, in contrast to IL-10, does not induce Ig production, due to absence of a functional IL-22 receptor on activated human B cells. Int Immunol. 2002 Nov;14(11):1351-6 Oncogenesis Aberrant expression of IL22RA1 in ALK+ALCL lymphoma cells allows these cells to be responsive to IL-22 stimulation, which further stimulate STAT3 signaling and the growth of these cells. Blocking the IL-22 signaling pathway using a neutralizing antibody has been shown to significantly decrease the growth of ALK+ALCL cells in-vitro. The aberrant expression of IL22RA1 in ALK+ALCL is dependent on the expression of NPM-ALK, since siRNA to downregulate NPM-ALK dramatically shut down IL22RA1 expression. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Wang M, Tan Z, Zhang R, Kotenko SV, Liang P. Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2. J Biol Chem. 2002 Mar 1;277(9):7341-7 Dumoutier L, Lejeune D, Hor S, Fickenscher H, Renauld JC. Cloning of a new type II cytokine receptor activating signal transducer and activator of transcription (STAT)1, STAT2 and STAT3. Biochem J. 2003 Mar 1;370(Pt 2):391-6 Amin HM, Lai R. Pathobiology of ALK+ anaplastic large-cell lymphoma. Blood. 2007 Oct 1;110(7):2259-67 1109 IL22RA1 (interleukin 22 receptor, alpha 1) Gelebart P, Lai R Bard JD, Gelebart P, Anand M, Amin HM, Lai R. Aberrant expression of IL-22 receptor 1 and autocrine IL-22 stimulation contribute to tumorigenicity in ALK+ anaplastic large cell lymphoma. Leukemia. 2008 Aug;22(8):1595-603 interleukin-22 receptor recruits STAT3 by interacting with its coiled-coil domain. J Biol Chem. 2009 Sep 25;284(39):2637784 Endam LM, Bossé Y, Filali-Mouhim A, Cormier C, Boisvert P, Boulet LP, Hudson TJ, Desrosiers M. Polymorphisms in the interleukin-22 receptor alpha-1 gene are associated with severe chronic rhinosinusitis. Otolaryngol Head Neck Surg. 2009 May;140(5):741-7 Bleicher L, de Moura PR, Watanabe L, Colau D, Dumoutier L, Renauld JC, Polikarpov I. Crystal structure of the IL-22/IL22R1 complex and its implications for the IL-22 signaling mechanism. FEBS Lett. 2008 Sep 3;582(20):2985-92 de Oliveira Neto M, Ferreira JR Jr, Colau D, Fischer H, Nascimento AS, Craievich AF, Dumoutier L, Renauld JC, Polikarpov I. Interleukin-22 forms dimers that are recognized by two interleukin-22R1 receptor chains. Biophys J. 2008 Mar 1;94(5):1754-65 This article should be referenced as such: Gelebart P, Lai R. IL22RA1 (interleukin 22 receptor, alpha 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):11061110. Dumoutier L, de Meester C, Tavernier J, Renauld JC. New activation modus of STAT3: a tyrosine-less region of the Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1110 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review MAPK7 (mitogen-activated protein kinase 7) Francisco de Asís Iñesta-Vaquera, Ana Cuenda Centro Nacional de Biotecnologia-CSIC, Department of Immunology and Oncology, Madrid, Spain (FdAIV, AC) Published in Atlas Database: February 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/MAPK7ID41294ch17p11.html DOI: 10.4267/2042/44909 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology (MAPK7a, b and c) have been reported. Mouse splice variants are generated by alternative splicing across introns 1 and/or 2 (Yan et al., 2001). Identity Other names: BMK1, ERK4, ERK5, PRKM7 HGNC (Hugo): MAPK7 Location: 17p11.2 Pseudogene DNA/RNA Protein Description Note ERK5, also known as MAPK7 or "Big MAP-Kinase 1" (BMK1) belongs to the Mitogen Activated Protein Kinase (MAPK) family, and therefore to the CGMC kinases in the human kinome (Manning et al., 2002). ERK5, at 98 kDa, is twice the size of other MAPKs and hence the largest kinase within its group. No human or mouse pseudogene known. The MAPK7 entire gene spans 5,82 kb on the short arm of chromosome 17. It contains 6 exons. Transcription The human MAPK7 gene encodes an 816 amino-acids protein of about 98 kDa. MAPK7 mRNA is 2445 bp. There are 11 transcripts, seven of which are protein coding. In mice, three splice variants MAPK7 genomic context (Chromosome 17; location 17p11.2). Genomic organization of MAPK7 gene on chromosome 17p11.2. The boxes indicate coding regions (exons 1-6) of the gene. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1111 MAPK7 (mitogen-activated protein kinase 7) Iñesta-Vaquera FdA, Cuenda A Schematic representation of the human ERK5 (MAPK7) protein domains. NES1 and NES2, bipartite nuclear exportation signal; PB1-BD, PB1 (Phox and Bem domain 1) binding domain; Kinase Domain, catalytic kinase domain; TEY, sequence motif containing ERK5 regulatory phosphorylation residues; PR-1 and PR-2, proline rich domains; Transcriptional trans-activation, transcriptional activity domain. It possesses a catalytic N-terminal domain, which share 50% homology with ERK1 (MAPK3) and ERK2 (MAPK1) and a unique C-terminal tail of about 400 amino-acids long. In vivo, ERK5 is activated to the same extent by environmental stresses, such as oxidative and osmotic shock, and by growth factors. In addition, ERK5 may be activated by the cytokine Interleukin-6 in B cells. Function Genetic studies have shown that ERK5 (MAPK7) is essential for cardiovascular development and neuronal differentiation. ERK5 knock-out mice die at midgestation due to developmental failures in structures as placenta, heart and vascular system (Regan et al., 2002; Sohn et al., 2002; Yan et al., 2003; Hayashi et al., 2004; Wang et al., 2005). ERK5 also regulates cell survival in a variety of tissues. At nervous system, ERK5 acts as a neuroprotector from neurotrophic factor withdrawal and toxic insults (Cavanaugh, 2004). Also, ERK5 is required to mediate the survival response of neurons to nerve growth factor (Finegan et al., 2009). In the immune system, the ERK5 pathway regulates apoptosis of developing thymocytes (Sohn et al., 2008) and protects B cells from proapoptotic stimuli (Carvajal-Vergara et al., 2005). ERK5 is also required for cell cycle progression. It regulates cyclin D1 expression (Mulloy et al., 2003) and is necessary for EGF-induced cell proliferation and progression through the cell cycle (Kato et al., 1998). Moreover, it has been suggested that the ERK5NFKappaB pathway may be required for a timely mitotic entry (Cude et al., 2007). Additionally, ERK5, along with other MAPK pathways can play an indirect role in cytoskeleton rearrangement (Barros and Marshall, 2005), in promoting SRC-induced podosome formation (Schramp et al., 2008), and in cell attachment to the extracellular matrix and in endothelial cell migration (Spiering et al., 2009; Sawhney et al., 2009). ERK5 (MAPK7) is a protein with kinase activity (in its N-terminal region) and also transcriptional activation activity (in the C-terminal half). Downstream targets of ERK5 include the transcription factors MEF2A, Description Human ERK5 (MAPK7) is a Ser/Thr protein kinase of 816 amino-acids with a predicted mass of 98 kDa. The ERK5 N-terminus domain resembles the typical MAPK catalytic domain and includes the MAPK-conserved TXY activation sequence (T218EY220) in the activation loop. The activation of ERK5 occurs via interaction with and dual phosphorylation in its TEY motif by MKK5 (Mody et al., 2003). MKK5 mediated ERK5 activation leads to ERK5 autophosphorylation in its unique C-terminal domain (Morimoto et al., 2007). Expression ERK5 (MAPK7) mRNA throughout all tissues. is widely expressed Localisation Both in tissues and in cultured cells, ERK5 (MAPK7) localizes to the cytoplasm of cells and/or to the nucleus. As shown in the above diagram, ERK5 molecule contains a bipartite nuclear exportation signal. In resting cells, the N- and C-terminal halves of ERK5 interact producing a nuclear export signal (NES) that retains ERK5 in the cytoplasm of the cells. Upon stimulation, the interaction between the N- and the Cterminal halves is disrupted, and therefore ERK5 enters the nucleus (Kondoh et al., 2006). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1112 MAPK7 (mitogen-activated protein kinase 7) Iñesta-Vaquera FdA, Cuenda A MEF2C and MEF2D, SAP1a, c-Myc and CREB. For example, ERK5 phosphorylates SAP1, which enhances its transcriptional activity promoting c-FOS expression (Terasawa et al., 2003), and activates the serum- and glucocorticoid-inducible kinase1 (SGK1) by phosphorylating Ser78 in response to growth factors (Hayashi et al., 2001). In cardiac tissue, ERK5 may couple cells electrically and metabolically by phosphorylating the gap-junction protein Cx43 at a key residue for gap junction communication (Cameron et al., 2003). Also, phosphorylated ERK5 regulates gene expression through its C-terminal transcriptional activation domain (Morimoto et al., 2007). References Kato Y, Tapping RI, Huang S, Watson MH, Ulevitch RJ, Lee JD. Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor. Nature. 1998 Oct 15;395(6703):713-6 Hayashi M, Tapping RI, Chao TH, Lo JF, King CC, Yang Y, Lee JD. BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoidinducible kinase. J Biol Chem. 2001 Mar 23;276(12):8631-4 Yan C, Luo H, Lee JD, Abe J, Berk BC. Molecular cloning of mouse ERK5/BMK1 splice variants and characterization of ERK5 functional domains. J Biol Chem. 2001 Apr 6;276(14):10870-8 Esparís-Ogando A, Díaz-Rodríguez E, Montero JC, Yuste L, Crespo P, Pandiella A. Erk5 participates in neuregulin signal transduction and is constitutively active in breast cancer cells overexpressing ErbB2. Mol Cell Biol. 2002 Jan;22(1):270-85 Homology ERK5 (MAPK7) N-terminal half shares a 50% sequence identity with ERK1/2. The homology of the C-terminal part of ERK5 with other protein has not been reported. ERK5 possesses ortholog in the majority of mammals (sharing 80-98% homology). In C. elegans, the SMA-5 protein is a 60% similar to human ERK5 (Watanabe et al., 2005). In Saccharomyces cerevisiae, Slt2p (Mpk1p) is an ERK5 ortholog (Truman et al., 2006). Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002 Dec 6;298(5600):1912-34 Regan CP, Li W, Boucher DM, Spatz S, Su MS, Kuida K. Erk5 null mice display multiple extraembryonic vascular and embryonic cardiovascular defects. Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9248-53 Sohn SJ, Sarvis BK, Cado D, Winoto A. ERK5 MAPK regulates embryonic angiogenesis and acts as a hypoxia-sensitive repressor of vascular endothelial growth factor expression. J Biol Chem. 2002 Nov 8;277(45):43344-51 Mutations Note Not identified. Cameron SJ, Malik S, Akaike M, Lerner-Marmarosh N, Yan C, Lee JD, Abe J, Yang J. Regulation of epidermal growth factorinduced connexin 43 gap junction communication by big mitogen-activated protein kinase1/ERK5 but not ERK1/2 kinase activation. J Biol Chem. 2003 May 16;278(20):18682-8 Implicated in Breast cancer Mody N, Campbell DG, Morrice N, Peggie M, Cohen P. An analysis of the phosphorylation and activation of extracellularsignal-regulated protein kinase 5 (ERK5) by mitogen-activated protein kinase kinase 5 (MKK5) in vitro. Biochem J. 2003 Jun 1;372(Pt 2):567-75 Note ERK5 (MAPK7) expression and activity is increased in breast cancer tumours. ERK5 overexpression has been established as an independent predictor of disease-free survival in breast cancer (Montero et al., 2009). In cell models, ERK5 has been linked to the regulation of breast cancer cells proliferation (Esparís-Ogando et al., 2002). Mulloy R, Salinas S, Philips A, Hipskind RA. Activation of cyclin D1 expression by the ERK5 cascade. Oncogene. 2003 Aug 21;22(35):5387-98 Terasawa K, Okazaki K, Nishida E. Regulation of c-Fos and Fra-1 by the MEK5-ERK5 pathway. Genes Cells. 2003 Mar;8(3):263-73 Prostatic cancer Yan L, Carr J, Ashby PR, Murry-Tait V, Thompson C, Arthur JS. Knockout of ERK5 causes multiple defects in placental and embryonic development. BMC Dev Biol. 2003 Dec 16;3:11 Note ERK5 (MAPK7) immunoreactivity is significantly upregulated in high-grade prostate cancer. Increased ERK5 cytoplasmic signals correlated with metastases and locally advanced disease at diagnosis. Strong nuclear ERK5 localization in prostatic tumours correlates with poor disease-specific survival (McCracken et al., 2008). Cavanaugh JE. Role of extracellular signal regulated kinase 5 in neuronal survival. Eur J Biochem. 2004 Jun;271(11):2056-9 Hayashi M, Kim SW, Imanaka-Yoshida K, Yoshida T, Abel ED, Eliceiri B, Yang Y, Ulevitch RJ, Lee JD. Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure. J Clin Invest. 2004 Apr;113(8):1138-48 Barros JC, Marshall CJ. Activation of either ERK1/2 or ERK5 MAP kinase pathways can lead to disruption of the actin cytoskeleton. J Cell Sci. 2005 Apr 15;118(Pt 8):1663-71 Hepatic carcinoma Note An increase in ERK5 (MAPK7) copy number was detected in primary HCC tumours. It has been suggested that MAPK7 is likely the target of 17p11 amplification and that the ERK5 protein promotes the growth of hepatic carcinoma cells by regulating mitotic entry (Zen et al., 2009). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Carvajal-Vergara X, Tabera S, Montero JC, Esparís-Ogando A, López-Pérez R, Mateo G, Gutiérrez N, Parmo-Cabañas M, Teixidó J, San Miguel JF, Pandiella A. Multifunctional role of Erk5 in multiple myeloma. Blood. 2005 Jun 1;105(11):4492-9 Wang X, Merritt AJ, Seyfried J, Guo C, Papadakis ES, Finegan KG, Kayahara M, Dixon J, Boot-Handford RP, Cartwright EJ, 1113 MAPK7 (mitogen-activated protein kinase 7) Iñesta-Vaquera FdA, Cuenda A Mayer U, Tournier C. Targeted deletion of mek5 causes early embryonic death and defects in the extracellular signalregulated kinase 5/myocyte enhancer factor 2 cell survival pathway. Mol Cell Biol. 2005 Jan;25(1):336-45 Sohn SJ, Lewis GM, Winoto A. Non-redundant function of Watanabe N, Nagamatsu Y, Gengyo-Ando K, Mitani S, Ohshima Y. Control of body size by SMA-5, a homolog of MAP kinase BMK1/ERK5, in C. elegans. Development. 2005 Jul;132(14):3175-84 Finegan KG, Wang X, Lee EJ, Robinson AC, Tournier C. Regulation of neuronal survival by the extracellular signalregulated protein kinase 5. Cell Death Differ. 2009 May;16(5):674-83 Kondoh K, Terasawa K, Morimoto H, Nishida E. Regulation of nuclear translocation of extracellular signal-regulated kinase 5 by active nuclear import and export mechanisms. Mol Cell Biol. 2006 Mar;26(5):1679-90 Montero JC, Ocaña A, Abad M, Ortiz-Ruiz MJ, Pandiella A, Esparís-Ogando A. Expression of Erk5 in early stage breast cancer and association with disease free survival identifies this kinase as a potential therapeutic target. PLoS One. 2009;4(5):e5565 the MEK5-ERK5 pathway in thymocyte apoptosis. EMBO J. 2008 Jul 9;27(13):1896-906 Truman AW, Millson SH, Nuttall JM, King V, Mollapour M, Prodromou C, Pearl LH, Piper PW. Expressed in the yeast Saccharomyces cerevisiae, human ERK5 is a client of the Hsp90 chaperone that complements loss of the Slt2p (Mpk1p) cell integrity stress-activated protein kinase. Eukaryot Cell. 2006 Nov;5(11):1914-24 Sawhney RS, Liu W, Brattain MG. A novel role of ERK5 in integrin-mediated cell adhesion and motility in cancer cells via Fak signaling. J Cell Physiol. 2009 Apr;219(1):152-61 Spiering D, Schmolke M, Ohnesorge N, Schmidt M, Goebeler M, Wegener J, Wixler V, Ludwig S. MEK5/ERK5 signaling modulates endothelial cell migration and focal contact turnover. J Biol Chem. 2009 Sep 11;284(37):24972-80 Cude K, Wang Y, Choi HJ, Hsuan SL, Zhang H, Wang CY, Xia Z. Regulation of the G2-M cell cycle progression by the ERK5NFkappaB signaling pathway. J Cell Biol. 2007 Apr 23;177(2):253-64 Zen K, Yasui K, Nakajima T, Zen Y, Zen K, Gen Y, Mitsuyoshi H, Minami M, Mitsufuji S, Tanaka S, Itoh Y, Nakanuma Y, Taniwaki M, Arii S, Okanoue T, Yoshikawa T. ERK5 is a target for gene amplification at 17p11 and promotes cell growth in hepatocellular carcinoma by regulating mitotic entry. Genes Chromosomes Cancer. 2009 Feb;48(2):109-20 Morimoto H, Kondoh K, Nishimoto S, Terasawa K, Nishida E. Activation of a C-terminal transcriptional activation domain of ERK5 by autophosphorylation. J Biol Chem. 2007 Dec 7;282(49):35449-56 McCracken SR, Ramsay A, Heer R, Mathers ME, Jenkins BL, Edwards J, Robson CN, Marquez R, Cohen P, Leung HY. Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer. Oncogene. 2008 May 8;27(21):2978-88 This article should be referenced as such: Iñesta-Vaquera FdA, Cuenda A. MAPK7 (mitogen-activated protein kinase 7). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1111-1114. Schramp M, Ying O, Kim TY, Martin GS. ERK5 promotes Srcinduced podosome formation by limiting Rho activation. J Cell Biol. 2008 Jun 30;181(7):1195-210 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1114 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review SLC16A1 (solute carrier family 16, member 1 (monocarboxylic acid transporter 1)) Céline Pinheiro, Fátima Baltazar Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal (CP, FB) Published in Atlas Database: February 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/SLC16A1ID44046ch1p13.html DOI: 10.4267/2042/44910 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Pseudogene Identity 1 related pseudogene identified - AKR7 family pseudogene (AFARP1), non-coding RNA. Other names: FLJ36745, HHF7, MCT, MCT1, MGC44475 HGNC (Hugo): SLC16A1 Location: 1p13.2 Protein Description DNA/RNA 500 amino acids; 53958 Da; 12 transmembrane domains, intracellular N- and C-terminal and a large intracellular loop between transmembrane domains 6 and 7. Note Human SLC16A1 was firstly cloned in 1994, by Garcia and colleagues. Structural gene organization as well as isolation and characterization of SLC16A1 promoter was achieved in 2002, by Cuff and Shirazi-Beechey. Expression Ubiquitous. Description Localisation 44507 bp lenght, containing 5 exons. Various SNPs have been described in SLC16A1 gene. Plasma membrane; also described in rat mitochondrial and peroxisomal membranes. Transcription Function 6 transcripts have been described for this gene (4 with protein product, 2 with no protein product): SLC16A1001 (5 exons; 3910 bps transcript length; 500 residues translation length); SLC16A1-002 (5 exons; 2101 bps transcript length; 456 residues translation length); SLC16A1-003 (4 exons; 865 bps transcript length; 215 residues translation length); SLC16A1-004 (2 exons; 452 bps transcript length; no translation product); SLC16A1-005 (4 exons; 1099 bps transcript length; 296 residues translation length); SLC16A1-006 (2 exons; 430 bps transcript length; no translation product). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Catalyses the proton-linked transport of metabolically important monocarboxylates such as lactate, pyruvate, branched-chain oxo acids derived from leucine, valine and isoleucine, and ketone bodies (acetoacetate, betahydroxybutyrate and acetate). Homology Belongs to the major facilitator superfamily (MFS). Monocarboxylate porter (TC 2.A.1.13) family. SLC16A1 gene is conserved in chimpanzee, dog, cow, mouse, rat, chicken, and zebrafish. 1115 SLC16A1 (solute carrier family 16, member 1 (monocarboxylic acid transporter 1)) Pinheiro C, Baltazar F Protein diagram drawn following UniProtKB/Swiss-Prot database prediction, using TMRPres2D software. associated with advanced gastric carcinoma, Lauren's intestinal type, TNM staging and lymph-node metastasis, in gastric cancer. Implicated in Various cancers Colorectal carcinoma Note MCT1/SLC16A1 has been described to be upregulated in a variety of tumours. Disease High grade glial neoplasms (Mathupala et al., 2004; Fang et al., 2006), colorectal (Koukourakis et al., 2006; Pinheiro et al., 2008), lung (Koukourakis et al., 2007), cervical (Pinheiro et al., 2008), and breast carcinomas (Pinheiro et al., in Press). Note MCT1/SLC16A1 has been described to be downregulated in colorectal carcinoma (Lamber et al., 2002). Erythrocyte lactate transporter defect Note Merezhinskaya et al. (2000) identified two heterozygous transitions in the SLC16A1 gene, in patients with erythrocyte lactate transporter defect: 610A-G transition (resulting in a lys204-to-glu (K204E) substitution in a highly conserved residue) and 1414G-A transition (resulting in a gly472-to-arg (G472R) substitution halfway along the cytoplasmic Cterminal chain). These substitutions are not conserved, but were not identified in 90 healthy control individuals. Erythrocyte lactate clearance in patients with these mutations was 40 to 50% that of normal control values. Breast cancer Prognosis In breast cancer, MCT1/SLC16A1 was found to be associated with poor prognostic variables such as basallike subtype and high grade tumours (Pinheiro et al., in Press). Oncogenesis SLC16A1 is expressed in normal breast tissue, but is silenced in breast cancer due to gene methylation (Asada et al., 2003). Hyperinsulinemic hypoglycemia familial 7 Gastric cancer Note The prognostic value of CD147 (a MCT1/SLC16A1 and MCT4/SLC16A3 chaperone required for plasma membrane expression and activity) was associated with MCT1/SLC16A1 co-expression in gastric cancer cells (Pinheiro et al., 2009). Prognosis Co-expression of MCT1/SLC16A1 with CD147 was Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Note Otonkoski et al. (2007) identified two heterozygotic alterations in the SLC16A1, in affected members of a Finnish family segregating autosomal dominant exercise-induced hyperinsulinemic hypoglycemia. First, a 163G-A transition in exon 1 located within a binding site for nuclear matrix protein-1 and predicted to disrupt the binding sites of 2 potential transcriptional 1116 SLC16A1 (solute carrier family 16, member 1 (monocarboxylic acid transporter 1)) Pinheiro C, Baltazar F Mathupala SP, Parajuli P, Sloan AE. Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: an in vitro study. Neurosurgery. 2004 Dec;55(6):14109; discussion 1419 repressors, and, secondly, a 25-bp insertion at nucleotide -24 introducing additional binding sites for the ubiquitous transcription factors SP1, USF and MZF1. The first variation leads to a 3-fold increase in transcription while the second variation leads to a 10fold increase in transcription. These mutations were not found in 92 Finnish and German controls. Fang J, Quinones QJ, Holman TL, Morowitz MJ, Wang Q, Zhao H, Sivo F, Maris JM, Wahl ML. The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high-risk neuroblastoma. Mol Pharmacol. 2006 Dec;70(6):2108-15 References Pinheiro C, Albergaria A, Paredes J, Sousa B, Dufloth R, Vieira D, Schmitt F, Baltazar F.. Monocarboxylate transporter 1 is upregulated in basal-like breast carcinoma. Histopathology In press Koukourakis MI, Giatromanolaki A, Harris AL, Sivridis E. Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res. 2006 Jan 15;66(2):632-7 Garcia CK, Li X, Luna J, Francke U. cDNA cloning of the human monocarboxylate transporter 1 and chromosomal localization of the SLC16A1 locus to 1p13.2-p12. Genomics. 1994 Sep 15;23(2):500-3 Koukourakis MI, Giatromanolaki A, Bougioukas G, Sivridis E. Lung cancer: a comparative study of metabolism related protein expression in cancer cells and tumor associated stroma. Cancer Biol Ther. 2007 Sep;6(9):1476-9 Brooks GA, Brown MA, Butz CE, Sicurello JP, Dubouchaud H. Cardiac and skeletal muscle mitochondria have a monocarboxylate transporter MCT1. J Appl Physiol. 1999 Nov;87(5):1713-8 Otonkoski T, Jiao H, Kaminen-Ahola N, Tapia-Paez I, Ullah MS, Parton LE, Schuit F, Quintens R, Sipilä I, Mayatepek E, Meissner T, Halestrap AP, Rutter GA, Kere J. Physical exercise-induced hypoglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic beta cells. Am J Hum Genet. 2007 Sep;81(3):467-74 Merezhinskaya N, Fishbein WN, Davis JI, Foellmer JW. Mutations in MCT1 cDNA in patients with symptomatic deficiency in lactate transport. Muscle Nerve. 2000 Jan;23(1):90-7 Pinheiro C, Longatto-Filho A, Ferreira L, Pereira SM, Etlinger D, Moreira MA, Jubé LF, Queiroz GS, Schmitt F, Baltazar F. Increasing expression of monocarboxylate transporters 1 and 4 along progression to invasive cervical carcinoma. Int J Gynecol Pathol. 2008 Oct;27(4):568-74 Cuff MA, Shirazi-Beechey SP. The human monocarboxylate transporter, MCT1: genomic organization and promoter analysis. Biochem Biophys Res Commun. 2002 Apr 12;292(4):1048-56 Pinheiro C, Longatto-Filho A, Scapulatempo C, Ferreira L, Martins S, Pellerin L, Rodrigues M, Alves VA, Schmitt F, Baltazar F. Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas. Virchows Arch. 2008 Feb;452(2):139-46 Lambert DW, Wood IS, Ellis A, Shirazi-Beechey SP. Molecular changes in the expression of human colonic nutrient transporters during the transition from normality to malignancy. Br J Cancer. 2002 Apr 22;86(8):1262-9 Pinheiro C, Longatto-Filho A, Simões K, Jacob CE, Bresciani CJ, Zilberstein B, Cecconello I, Alves VA, Schmitt F, Baltazar F. The prognostic value of CD147/EMMPRIN is associated with monocarboxylate transporter 1 co-expression in gastric cancer. Eur J Cancer. 2009 Sep;45(13):2418-24 Asada K, Miyamoto K, Fukutomi T, Tsuda H, Yagi Y, Wakazono K, Oishi S, Fukui H, Sugimura T, Ushijima T. Reduced expression of GNA11 and silencing of MCT1 in human breast cancers. Oncology. 2003;64(4):380-8 McClelland GB, Khanna S, González GF, Butz CE, Brooks GA. Peroxisomal membrane monocarboxylate transporters: evidence for a redox shuttle system? Biochem Biophys Res Commun. 2003 Apr 25;304(1):130-5 This article should be referenced as such: Pinheiro C, Baltazar F. SLC16A1 (solute carrier family 16, member 1 (monocarboxylic acid transporter 1)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1115-1117. Halestrap AP, Meredith D. The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch. 2004 Feb;447(5):61928 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1117 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review STOML2 (stomatin (EPB72)-like 2) Wenfeng Cao, Liyong Zhang, Fang Ding, Zhumei Cui, Zhihua Liu State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China (WC, LZ, DF, ZL); Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China (WC); Department of Obstetrics and Gynecology, Affiliated Hospital of Medical College, Qingdao University, Qingdao 266011, China (ZC) Published in Atlas Database: February 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/STOML2ID44346ch9p13.html DOI: 10.4267/2042/44911 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology frame however, commonly forms a 356 amino acid residue polypeptide with a predicted molecular weight of 38.5 kDa. Similar to other family members, SLP-2 as well as the stomatin from other species shares a characteristic NH2-terminal hydrophobic domain as well as a consensus cognate stomatin signature sequence that defines the stomatin gene family, however, it lacks the NH2-terminal hydrophobic domain (Wang et al., 2000). The SLP-2 protein contains an alanine-rich domain and a number of potential protein kinase C phosphorylation sites, cAMP-and-cGMP-dependent protein kinase phosphorylation sites and casein kinase II phosphorylation sites. Identity Other names: HSPC108, SLP-2 HGNC (Hugo): STOML2 Location: 9p13.3 DNA/RNA Description The gene encoding SLP-2 was 3250 bp long and consisted of ten exons interrupted by nine introns. Transcription There are 5 transcripts in this gene. However, a single 1.3 kb mRNA transcript encoding SLP-2 was ubiquitously expressed, and the translation length is 356 residues (Owczarek et al., 2001). Expression SLP-2 is widely expressed in many tissues and thought as a new component of the peripheral membrane skeleton. Especially, in the erythrocyte membrane, it also appears to exist at least partially as an oligomeric protein complex. The overexpression of SLP-2 can be found in many kinds of human tumors, such as esophageal squamous cell carcinoma, laryngeal squamous cell carcinoma, endometrial adenocarcinoma, and lung cancer. Pseudogene No known pseudogenes. Protein Description NP_038470; 356 aa. Human SLP-2 is presented on chromosome 9p13. The sequence at the 5'-end of the mRNA is interesting for the presence of three potential ATG initiator sites, all sharing the same open reading Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Localisation Predominantly on plasma membrane and in the cytoplasm. 1118 STOML2 (stomatin (EPB72)-like 2) Cao W, et al. Figure A. ALA-RICH, Alanine-rich region profile: 224-274: score = 8.657. Figure B. MYRISTYL, N-myristoylation site: 16-21: GSllAS, 31-36: GLprNT, 209-214: GTreSA, 314-319: GVvgAL, 326-331: GTpdSL, 341-346: GtdaSL; PKC-PHOSPHO-SITE, Protein kinase C phosphorylation site: 21-23: SgR, 78-80: SlK, 133-135: TmR, 335-337: SsR; CAMP-PHOSPHO-SITE, Camp-and-cGMPdependent protein kinase phosphorylation site: 26-29: RRaS, 200-203: KRaT; CK2-PHOSPHO-SITE, Casein kinase II phosphorylation site: 78-81: SlkE, 156-159: SivD, 203-206: TvlE, 229-232: SeaE, 277-280: TvaE, 335-338: SsrD, 345-348: SldE; ASNGLYCOSYLATION, N-glycosylation site: 96-99: NVTL, 154-157: NASI; AMIDATION, amidation site: 219-222: eGKK. number of different cancers, including esophageal squamous cell carcinoma (ESCC), laryngeal squamous cell carcinoma (LSCC), endometrial adenocarcinoma (EAC), lung cancer (LC) and breast cancer (see below). Function Human SLP-2 protein with unknown function, we hypothesize that SLP-2 may link stomatin or other integral membrane proteins to the peripheral cytoskeleton and thereby play a role in regulating ion channel conductances or the organization of sphingolipid and cholesterol-rich lipid rafts. Some recent results indicated that SLP-2 protein can significantly influence on multi-tumor progression, which allowed us to identify this unwell-known gene that maybe modulate invasion and metastasis of different cancers. Esophageal squamous cell carcinoma (ESCC) Prognosis As shown in human ESCC, a significant correlation exists between SLP-2 protein high expression and the depth of ESCC invasion (P=0.033) (Wang et al., 2009). Also, decreased cell growth and tumorigenesis in the antisense transfectants revealed that SLP-2 may be important in ESCC tumorigenesis (Zhang et al., 2006). Homology SLP-2 is one of the members of the Stomatin superfamily, among which identified vertebrate homologues are SLP-1, SLP-2, and SLP-3. SLP-1 is most abundant in brain and shares many similarities with UNC-24 (STOML1). SLP-3 is specifically expressed in olfactory sensory neurons (Seidel et al., 1998; Goldstein et al., 2003). Laryngeal squamous cell carcinoma (LSCC) Prognosis In addition, SLP-2 takes part in human LSCC malignant phenotype formation and development. High-level expression of SLP-2 protein could contribute to the prognostic characteristics of lymph node metastasis in human LSCC (Cao et al., 2007). Mutations Breast cancer No mutations have been reported for SLP-2. Mutation detection of SLP-2 exons was done using PCR and automated sequencing with 30 patient-matched human esophageal cancer tissues. No mutation was found within the open-reading frame of SLP-2 after sequencing results were aligned by the procedure SeqMan of DNAStar software (Zhang et al., 2006). Prognosis High-level expression of SLP-2 protein shows a worse prognosis, including increase in tumor size, progress in clinical stage, and appearance of lymph node and/or distant metastasis and is associated with decreased overall survival (P=0.011). Moreover, SLP-2 can be strongly associated with another important prognostic factor, HER-2/neu protein expression, which shows that they may act as dependent prognostic factors to indicate poor prognosis (Cao et al., 2007). Implicated in Various cancers Note SLP-2 has been shown to be over-expressed in a Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1119 STOML2 (stomatin (EPB72)-like 2) Cao W, et al. Owczarek CM, Treutlein HR, Portbury KJ, Gulluyan LM, Kola I, Hertzog PJ. A novel member of the STOMATIN/EPB72/mec-2 family, stomatin-like 2 (STOML2), is ubiquitously expressed and localizes to HSA chromosome 9p13.1. Cytogenet Cell Genet. 2001;92(3-4):196-203 Endometrial adenocarcinoma Prognosis Similarly, SLP-2 is also overexpressed in human endometrial adenocarcinoma (EAC) at both mRNA and protein level. Sense transfection of SLP-2 in EAC cell line accelerated cell growth whereas the antisense transfection reduced cell growth in vitro (Cui et al., 2007). Goldstein BJ, Kulaga HM, Reed RR. Cloning and characterization of SLP3: a novel member of the stomatin family expressed by olfactory receptor neurons. J Assoc Res Otolaryngol. 2003 Mar;4(1):74-82 Zhang L, Ding F, Cao W, Liu Z, Liu W, Yu Z, Wu Y, Li W, Li Y, Liu Z. Stomatin-like protein 2 is overexpressed in cancer and involved in regulating cell growth and cell adhesion in human esophageal squamous cell carcinoma. Clin Cancer Res. 2006 Mar 1;12(5):1639-46 Lung cancer Prognosis At last, SLP-2 was overexpressed in human lung cancer (Zhang et al., 2006). High-level SLP-2 expression was significantly correlated with distant metastasis, decreased overall survival and disease-free survival. SLP-2 overexpression was an independent prognostic factor in multivariate analysis using the Cox regression model (p<0.05) (Chang et al., 2009). Cao W, Zhang B, Liu Y, Li H, Zhang S, Fu L, Niu Y, Ning L, Cao X, Liu Z, Sun B. High-level SLP-2 expression and HER2/neu protein expression are associated with decreased breast cancer patient survival. Am J Clin Pathol. 2007 Sep;128(3):430-6 Cao WF, Zhang LY, Liu MB, Tang PZ, Liu ZH, Sun BC. Prognostic significance of stomatin-like protein 2 overexpression in laryngeal squamous cell carcinoma: clinical, histologic, and immunohistochemistry analyses with tissue microarray. Hum Pathol. 2007 May;38(5):747-52 Mitochondrial component Note SLP-2 localizes in mitochondria, affects mitochondrial membrane potential (MMP) and ATP production. Hence, SLP-2 is a mitochondrial protein and therefore, functions in energy process by MMP maintenance, and subsequently affecting cell motility, proliferation and chemosensitivity (Wang et al., 2009). Cui Z, Zhang L, Hua Z, Cao W, Feng W, Liu Z. Stomatin-like protein 2 is overexpressed and related to cell growth in human endometrial adenocarcinoma. Oncol Rep. 2007 Apr;17(4):82933 References Wang Y, Cao W, Yu Z, Liu Z. Downregulation of a mitochondria associated protein SLP-2 inhibits tumor cell motility, proliferation and enhances cell sensitivity to chemotherapeutic reagents. Cancer Biol Ther. 2009 Sep;8(17):1651-8 Seidel G, Prohaska R. Molecular cloning of hSLP-1, a novel human brain-specific member of the band 7/MEC-2 family similar to Caenorhabditis elegans UNC-24. Gene. 1998 Dec 28;225(1-2):23-9 Chang D, Ma K, Gong M, Cui Y, Liu ZH, Zhou XG, Zhou CN, Wang TY. SLP-2 overexpression is associated with tumour distant metastasis and poor prognosis in pulmonary squamous cell carcinoma. Biomarkers. 2010 Mar;15(2):104-10 Wang Y, Morrow JS. Identification and characterization of human SLP-2, a novel homologue of stomatin (band 7.2b) present in erythrocytes and other tissues. J Biol Chem. 2000 Mar 17;275(11):8062-71 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) This article should be referenced as such: Cao W, Zhang L, Ding F, Cui Z, Liu Z. STOML2 (stomatin (EPB72)-like 2). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1118-1120. 1120 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review AMOT (angiomotin) Roshan Mandrawalia, Ranjan Tamuli Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati-781 039, Assam, India (RM, RT) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/AMOTID632chXq23.html DOI: 10.4267/2042/44912 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology (261), 721-751 (31), a PDZ-binding motif 1081-1084 (4), a SMC_prok_B region 429-549 (121), and an angiomotin_C terminal 599-794 (196). Phosphorylations occur on S305, S312, S712, S714, T717, Y719, and T1061. Phosphorylated upon DNA damage, probably by ATM or ATR. Isoforms: - Isoform 1: p130 angiomotin 1084 amino acids, 118085 Da. This isoform has been chosen as the 'canonical' sequence. - Isoform 2: p80 angiomotin 675 amino acids, 72540 Da. The isoform differs from the canonical sequence with N-terminal alternative splicing region 1-409 (409) missing, which mediates the binding of angiomotin to F-actin stress fibres. The SMC_prok_B region is also missing in this isoform. Identity Other names: KIAA1071 HGNC (Hugo): AMOT Location: Xq23 DNA/RNA Description DNA size 66.31 kb, mRNA size 6888 bp, 12 exons. Protein Description Angiomotin protein is 1084 amino acid residues in length. It contains two coiled coil domains 429-689 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1121 AMOT (angiomotin) Mandrawalia R, Tamuli R acids from PDZ-binding motif results in inhibition of chemotaxis, embryos with this mutation may lead to death on embryonic day 9.5. Expression Expressed in placenta and skeletal muscle. Predominantly expressed in endothelial cells of capillaries, larger vessels of the placenta. Implicated in Localisation Breast cancer Cell junction, tight junction. Localized on the cell surface. May act as a transmembrane protein. Note Angiomotin is linked to angiogenesis and aggressive nature of breast tumours. Angiomotin shows high level of expression in mammary tissues during tumour stages as compared to normal expression level (33.1 ± 11 in normal versus 86.5 ± 13.7 in tumour tissues, p=0.0003). Significant high expression was found in aggressive tumours (grade 2, grade 3 and with nodal involvement) compared with less aggressive grade 1 tumour (p<0.001 and p=0.05 respectively). Angiogenesis is the essential process in the development and spread of breast cancer, by providing blood supply to tumours and escape route for tumour cells to other part of the body. Function Mediates inhibitory effect of angiostatin on tube formation and the migration of endothelial cells toward growth factors during the formation of new blood vessels in the larger vessels of the placenta. Isoform-1 is found to control cell shape by association with Factin fibres through N-terminal part of protein. The isoform 2 (p80) promotes angiogenesis, in part, by conferring a hypermigratory phenotype to endothelial cells. Homology The percent identity below represents identity of AMOT over an aligned region in Unigene. Mus musculus: 88.1 (percent identity) Oryctolagus cuniculus: 79 Sus scrofa: 72 Danio rerio: 68.9 Fugu rubripes: 65 Xenopus laevis: 61.8 Caenorhabditis elegans: 46 Saccharomyces cerevisiae: 47 Drosophila melanogaster: 36 Hemangioendothelioma invasion Disease Angiomotin expression promotes hemangioendothelioma invasion. Expression of human angiomotin in mouse aortic endothelial (MAE) cells results in stabilization of tubes in the Matrigel assay. Cells from the established tubes invaded into the solidified matrigel, however, cells expressing a functional mutant lacking the PDZ protein interaction motif did not migrate and form tubes. Angiomotin may promote angiogenesis by both stimulating invasion as well as stabilizing established tubes. Mutations Endothelial cell migration and tube formation Note Several polymorphisms have been found but none of them has shown any association with a disease. Furthermore, endothelial cells expressing mutated angiomotins have been reported failure in their function, including failure to migrate and inhibition of angiogenesis. Mutation with deletion of three amino Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Note Upon expression of angiomotin in HeLa cells, angiomotin bound and internalized fluorescein-labeled angiostatin, a circulating inhibitor of angiogenesis. In endothelial cells, angiomotin protein is localized to the 1122 AMOT (angiomotin) Mandrawalia R, Tamuli R Ernkvist M, Aase K, Ukomadu C, Wohlschlegel J, Blackman R, Veitonmäki N, Bratt A, Dutta A, Holmgren L. p130-angiomotin associates to actin and controls endothelial cell shape. FEBS J. 2006 May;273(9):2000-11 leading edge of migrating cells and results in increased cell migration. Angiomotin-transfected MAE cells bind and respond to angiostatin by inhibition of cell migration and tube formation, which suggest that angiomotin regulates endothelial cell migration and tube formation. Holmgren L, Ambrosino E, Birot O, Tullus C, Veitonmäki N, References Levchenko T, Carlson LM, Musiani P, Iezzi M, Curcio C, Forni G, Cavallo F, Kiessling R. A DNA vaccine targeting angiomotin inhibits angiogenesis and suppresses tumor growth. Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9208-13 Troyanovsky B, Levchenko T, Månsson G, Matvijenko O, Holmgren L. Angiomotin: an angiostatin binding protein that regulates endothelial cell migration and tube formation. J Cell Biol. 2001 Mar 19;152(6):1247-54 Jiang WG, Watkins G, Douglas-Jones A, Holmgren L, Mansel RE. Angiomotin and angiomotin like proteins, their expression and correlation with angiogenesis and clinical outcome in human breast cancer. BMC Cancer. 2006 Jan 23;6:16 Zetter BR. Hold that line. Angiomotin regulates endothelial cell motility. J Cell Biol. 2001 Mar 19;152(6):F35-6 Wells CD, Fawcett JP, Traweger A, Yamanaka Y, Goudreault M, Elder K, Kulkarni S, Gish G, Virag C, Lim C, Colwill K, Starostine A, Metalnikov P, Pawson T. A Rich1/Amot complex regulates the Cdc42 GTPase and apical-polarity proteins in epithelial cells. Cell. 2006 May 5;125(3):535-48 Bratt A, Wilson WJ, Troyanovsky B, Aase K, Kessler R, Van Meir EG, Holmgren L. Angiomotin belongs to a novel protein family with conserved coiled-coil and PDZ binding domains. Gene. 2002 Sep 18;298(1):69-77 Ernkvist M, Luna Persson N, Audebert S, Lecine P, Sinha I, Liu M, Schlueter M, Horowitz A, Aase K, Weide T, Borg JP, Majumdar A, Holmgren L. The Amot/Patj/Syx signaling complex spatially controls RhoA GTPase activity in migrating endothelial cells. Blood. 2009 Jan 1;113(1):244-53 Levchenko T, Aase K, Troyanovsky B, Bratt A, Holmgren L. Loss of responsiveness to chemotactic factors by deletion of the C-terminal protein interaction site of angiomotin. J Cell Sci. 2003 Sep 15;116(Pt 18):3803-10 Gagné V, Moreau J, Plourde M, Lapointe M, Lord M, Gagnon E, Fernandes MJ. Human angiomotin-like 1 associates with an angiomotin protein complex through its coiled-coil domain and induces the remodeling of the actin cytoskeleton. Cell Motil Cytoskeleton. 2009 Sep;66(9):754-68 Levchenko T, Bratt A, Arbiser JL, Holmgren L. Angiomotin expression promotes hemangioendothelioma invasion. Oncogene. 2004 Feb 19;23(7):1469-73 Bratt A, Birot O, Sinha I, Veitonmäki N, Aase K, Ernkvist M, Holmgren L. Angiomotin regulates endothelial cell-cell junctions and cell motility. J Biol Chem. 2005 Oct 14;280(41):34859-69 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) This article should be referenced as such: Mandrawalia R, Tamuli R. AMOT (angiomotin). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1121-1123. 1123 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review BRCA2 (breast cancer 2, early onset) Frédéric Guénard, Francine Durocher Cancer Genomics Laboratory, Oncology and Molecular Endocrinology Research Centre, CRCHUL, CHUQ and Laval University, Quebec, G1V 4G2, Canada (FG, FD) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/BRCA2ID164ch13q13.html DOI: 10.4267/2042/44913 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology The N-terminal part of the BRCA2 protein contains a transcriptional activation domain (aa 18-105). BRCA2 exon 11 encodes eight conserved motifs termed BRC repeats. Each of these repeats is composed of about 30 residues. A DNA-binding domain has been located in the Cterminal region of the BRCA2 protein (aa 2478-3185). It is composed of a conserved helical domain and three OB folds. Two nuclear localization signals (NLS) have been identified in the C-terminal region of BRCA2. Identity Other names: BRCC2, BROVCA2, FACD, FAD, FAD1, FANCB, FANCD, FANCD1, GLM3 HGNC (Hugo): BRCA2 Location: 13q13.1 DNA/RNA Description The BRCA2 gene is composed of 27 exons and spans approximately 84.2 kb of genomic DNA. Expression Protein BRCA2 expression is proportional to the rate of cell proliferation. Non-dividing cells do not express BRCA2 while wide expression of BRCA2 was observed in actively dividing tissues, including the epithelium of the breast during puberty and pregnancy. The BRCA2 expression is regulated during the cell cycle, with highest expression during the S phase of the cell cycle. Most of the BRCA2 proteins are associated to DSS1. The presence of DSS1 was demonstrated to stabilize the BRCA2 protein. Description Localisation Human BRCA2 protein is composed of 3418 amino acids (384 kDa). BRCA2 is a nuclear protein. Transcription The BRCA2 gene encodes a 11386 bp mRNA transcript. Transcription site is located 227 bp upstream the first ATG of the BRCA2 ORF. The translation start site is located in exon 2. Pseudogene No pseudogene reported. Structure of BRCA2. BRCA2 is a 3418 aa protein. BRC repeats: BRCA C-terminal repeats; NLS: Nuclear localization signals. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1124 BRCA2 (breast cancer 2, early onset) Guénard F, Durocher F BRCA2 mutations, pancreatic cancer. Function BRCA2 has been implicated in maintenance of genomic integrity and in the cellular response to DNA damage. The BRCA2 protein interacts with the RAD51 recombinase to regulate homologous recombination (HR). BRCA2 regulates the intracellular localization of RAD51. It also targets the RAD51 to ssDNA and inhibits dsDNA binding, thus regulating/enhancing DNA strand exchange activity of RAD51. CHEK1 and CHEK2 both phosphorylate the RAD51/BRCA2 complex and regulate the functional association of this complex in response to DNA damage. BRCA2 is also implicated in cell cycle checkpoints. Following exposure to X-rays or UV light, cells expressing truncated BRCA2 protein exhibit arrest in the G1 and G2/M phases. BRCA2 protein plays a role in mitotic spindle assembly checkpoints through modulation of the level of spindle assembly checkpoint proteins including Aurora A and Aurora B. A role in regulation of transcription has been attributed to BRCA2. BRCA2 binding to the DSS1 protein appears to be required for proper completion of cell division in yeast. The BRCA2 protein demonstrated the ability to stimulate transcription. For example, exogenous expression of BRCA2 can stimulate transcription of androgen receptor-regulated genes. This function of BRCA2 is regulated by the binding of the EMSY protein to the region of BRCA2 responsible for transcriptional activation. An excess of EMSY results in silencing of BRCA2-driven transcriptional activation. BRCA2 localizes to meiotic chromosomes during early meiotic prophase I when homologous chromosomes undergo synapsis. Moreover, BRCA2 interacts with the meiosis-specific recombinase DMC1, thus implicating BRCA2 in meiotic recombination. for prostate and Somatic Somatic mutations in BRCA2 are infrequent in sporadic breast cancer. Methylation of the BRCA2 promoter has not been detected in normal tissues nor in breast and ovarian cancers. Loss of heterozygosity at the BRCA2 locus has been frequently found in sporadic breast and ovarian tumors. Implicated in Breast cancer Note Informations regarding breast cancer and BRCA2 mutations and polymorphisms are available in a central repository formed by the National Human Genome Research; National Institute of Health. This repository, named Breast Cancer Information Core (BIC) NHGRI, is available at the following address: http://research.nhgri.nih.gov/bic/. Disease Breast tumors in BRCA2 carriers are found at higher histologic grade (2 and 3) than sporadic tumors. Tumors from BRCA2 carriers are more commonly found to be stage IV than sporadic control tumors and BRCA2-associated breast cancer cases are more often node-positive than control breast cancer cases. Prognosis BRCA2 mutation carriers show younger mean age at diagnosis than sporadic breast cancer cases. Bilateral breast cancer is found more commonly in BRCA2associated breast cancer than in sporadic breast cancer. ER and PR expression in BRCA2 tumors are similar than in control tumors, which contrasts with ER and PR expression found in BRCA1 tumors. Oncogenesis It was suggested that genomic rearrangements account for 7.7% of the BRCA2 mutation spectrum. Loss of the wild-type allele is not required for breast tumorigenesis in BRCA2 mutation carriers. Somatic mutations of the BRCA2 gene are an infrequent event in sporadic breast cancer tumors. Loss of heterozygosity at the BRCA2 locus on chromosome 13q12-q13 was observed in approximately 30% of sporadic breast cancer. Methylation of the CpG dinucleotide within the BRCA2 promoter is not found in normal and neoplastic breast tissues. Homology BRCA2 homologs have been found in a diverse range of organisms. In addition to zebrafish and C. elegans, homologs exist in diverse eukaryotes, from plants to parasitic organisms. Low general conservation is found in BRCA2. Higher level of homology is observed for several segments, including transactivation domain, BRC repeats and nuclear localization signals located within C-terminal region. Mutations Male breast cancer Germinal Note A cumulative risk of 6% and 7% of developing breast cancer by the age of 70 and 80, respectively, has been estimated for male BRCA2 mutation carriers. BRCA2 mutations have been found in 14% of familial male breast cancer and 4% of unselected male breast cancer cases. High risk of breast and ovarian cancer is associated with germline BRCA2 mutations. Cumulative risk of breast cancer in BRCA2 mutation carriers was estimated to 45% by the age of 70 years while ovarian cancer risk in carriers was estimated to 11%. Increased risk of several other cancers are associated with Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) especially 1125 BRCA2 (breast cancer 2, early onset) Guénard F, Durocher F truncating mutations in these families. However, a small study conducted on a limited number of families found BRCA2 mutations in two families. Incomplete segregation of the mutation with the disease was found in these families as affected brothers did not carry these mutations. Prognosis BRCA2 mutation carriers have a significantly lower mean age at diagnosis of prostate cancer and shorter mean survival time than non-carriers. BRCA2 mutation carriers show more advanced tumor stage and higher grade at diagnosis. Prostate cancer carriers of a BRCA2 mutation show poorer survival than BRCA1 carriers. Prostate cancer patients which are carriers of the 999del5 Icelandic founder mutation appear to have worse prognosis than non-carriers of this mutation. Histopathological features of prostate cancer in BRCA2 mutation carriers revealed that prostate cancer developed in mutation carriers show higher Gleason scores in than non-carriers. Oncogenesis Allelic loss at the BRCA2 locus was identified in a majority of prostate tumor samples from carriers of the c.999del5 mutation, thus suggesting that no functional BRCA2 protein is found in these tumors. Disease Male breast cancers are mostly ductal or unclassified carcinomas. Papillary, mucinous and lobular carcinomas each represent less than 3% of male breast cancers. Estrogen receptor and progesterone receptor expression is found in approximately 90% and 81% of male breast cancers, respectively. Prognosis Overall survival rates for male breast cancers are lower than for female breast cancers due to the older age and more advances disease at the time of diagnosis. Male breast cancers associated with BRCA2 mutation are diagnosed at younger age than sporadic male breast cancer cases. Ovarian cancer Note Carriers of mutations in the central portion of BRCA2, termed OCCR (ovarian cancer cluster region; aa 10122210), are at higher risk of ovarian cancer and lower breast cancer risk than carriers of mutations outside the OCCR. Disease Ovarian cancer is mostly epithelial tumors (90%) and lifetime risk of ovarian cancer in the general population is estimated to be 1-1.5%. Risk of ovarian cancer in BRCA2 mutation carriers is estimated to be 10%. Prognosis BRCA2 ovarian tumors are similar to BRCA1 ovarian tumors as these two types of tumors are more likely to be serous adenocarcinomas and higher grade than control tumors. BRCA2-associated ovarian cancers occur later in life than BRCA1-related or control ovarian tumors. Oncogenesis Complete loss of the wild-type BRCA2-allele is observed in BRCA2-associated ovarian cancers. Loss of heterozygosity at 13q12-q14 is also observed in sporadic epithelial ovarian tumors. On the other hand, CpG dinucleotide methylation of the BRCA2 promoter is not found in sporadic ovarian cancers. Stomach cancer Note Stomach cancer was reported in family members of women with ovarian cancer carrying a BRCA2 mutation within the OCCR. On the other hand, the presence of stomach cancer in relatives of ovarian cancer cases is strongly predictive of the presence of a BRCA2 mutation. Specifically, the BRCA2 999del5 mutation is associated with an increased risk of stomach cancer in first- and second-degree relatives. Assessment of the presence of non-breast or ovarian cancers in BRCA2 mutation carriers estimated a relative risk of stomach cancer of 2.59 to be associated with BRCA2 mutations. Meta-analysis of published studies latter confirmed increased risk of stomach cancer in BRCA2 carriers. Prostate cancer Pharyngeal cancer Note Different studies conducted on BRCA2 mutation carriers revealed an increased risk of prostate cancer in BRCA2 mutation carriers. Relative risk associated with BRCA2 mutations is estimated to be approximately 2.5 to 5. Protein-truncating BRCA2 mutations are associated with early-onset prostate cancer. Different studies revealed that BRCA2 mutations are responsible for less than 1% of early-onset prostate cancer in the US Caucasian population while such mutations are responsible for 2.3% of early-onset prostate cancer diagnosed in United Kingdom. Most studies conducted on hereditary prostate cancer families did not revealed a contribution of BRCA2 Note An increased risk of buccal cavity and pharynx cancer was suggested during the assessment of cancers other than breast and ovarian cancer in BRCA2 mutation carriers. This was thereafter confirmed in a cohort of BRCA2 mutation carriers leading to the estimation of a relative risk of 7.3 (95% CI = 2.0 - 18.6). Higher relative risk of pharyngeal cancer is found for carriers younger than 65 years old. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Gallbladder and bile duct cancer Note Evaluation of risks of cancers other than breast and 1126 BRCA2 (breast cancer 2, early onset) Guénard F, Durocher F their relatives, other studies did not confirm this association. ovarian cancers in BRCA2 carriers found a higher risk of gallbladder and bile duct cancer in BRCA2 carriers (RR = 4.97; 95% CI = 1.50-16.52). Specifically, the 6167delT Jewish Ashkenazi founder BRCA2 mutation was observed at significantly higher rate in bile duct cancer cases than in population controls. Bone cancer Note An excess risk of bone cancer (RR = 14.4; 95% CI = 2.9 - 42.1) was observed in a cohort of BRCA2 mutation carriers from the Netherlands. Colon cancer Note It was reported that risk of colorectal cancer in firstdegree relatives of BRCA2 mutation carriers affected with ovarian cancer is increased by threefold for BRCA2 mutations located within the OCCR. Analysis of a BRCA2 mutation in different families led to the suggestion that BRCA2 mutations predispose to colon cancer. It was thereafter reported that BRCA2 mutation carriers are at increased risk of colon cancer before the age of 65 years old. The association of BRCA2 mutations with colon cancer was latter confirmed in a meta-analysis. Fanconi anemia (complementation group D1) Note Biallelic mutations of the BRCA2 gene are responsible for Fanconi anemia subgroup D1 (FA-D1). Disease Fanconi anemia (FA) is a rare recessive disease characterized by various clinical features. Many developmental defects are found in FA patients. Radial aplasia, microcephaly, microphthalmia, small stature, skin hyperpigmentation and malformation of the kidneys are encountered in FA patients. Very high frequency of bone marrow failure, leukemia and squamous cell carcinoma of the head and neck as well as gynecological squamous cell carcinoma are associated with FA. Bone marrow failure generally leads to aplastic anemia during the first decade of life. Esophageal carcinoma and liver, brain, skin and renal tumors are also found in FA patients. Prognosis The FA-D1 and FA-N subgroups are clinically different from other FA subgroups as these subgroups are associated with increased predisposition to solid childhood malignancies such as medulloblastoma and Wilms tumor. Cytogenetics At the cellular level, FA is a chromosomal fragility syndrome. FA cells are hypersensitive to DNA interstrand crosslinking agents such as mitomycin C, diepoxybutane and cisplatin. In addition to hypersensitivity to these agents, FA cells show an increased number of spontaneous breaks. Pancreas cancer Note Different studies suggested that BRCA2 mutations are associated with less than 1% of sporadic pancreatic cancer in Caucasians while such mutations could account for 10% of sporadic pancreatic cancer in Ashkenazi Jewish population. Approximately 10% of patients developing pancreatic cancer show patterns of hereditary predisposition. Screening of BRCA2 mutations in familial pancreatic cancer cases suggested that BRCA2 mutations account for 6-17% of these families. Following the identification of germline BRCA2 mutations in pancreatic cancer, it was evaluated that BRCA2 mutations confer roughly a 3.5-folds increased risk. Relative risk of pancreatic cancer was found to be higher at younger age (younger than 65 years old). Different studies evaluated the lifetime risk of pancreatic cancer in BRCA2 mutation carriers to be approximately 5%. Prognosis Among human malignancies, pancreatic cancer has one of the worst prognoses. 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Nat Struct Mol Biol. 2007 Jun;14(6):468-74 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) This article should be referenced as such: Guénard F, Durocher F. BRCA2 (breast cancer 2, early onset). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):11241131. 1131 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review FST (follistatin) Michael Grusch Medical University of Vienna, Department of Medicine I, Institute of Cancer Research, Borschkegasse 8a, A-1090 Vienna, Austria (MG) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/FSTID44477ch5q11.html DOI: 10.4267/2042/44914 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology rise to two main transcripts of 1122 bp (transcript variant FST344) and 1386 bp (transcript variant FST317). The first exon encodes the signal peptide, the second exon the N-terminal domain and exons 3-5 each code for a follistatin module. Alternative splicing leads to usage of either exon 6A, which codes for an acidic region in FST344 or exon 6B, which contains two bases of the stop codon of FST317 (Shimasaki et al., 1988). Identity Other names: FS HGNC (Hugo): FST Location: 5q11.2 Local order RPS19P4 (ribosomal protein S19 pseudogene 4) - FST - NDUFS4 (NADH dehydrogenase (ubiquinone) Fe-S protein 4). Transcription DNA/RNA Transcription of FST mRNA was shown to be stimulated by TGF beta and activin A via Smad proteins (Bartholin et al., 2002), which seems to be part of a negative feedback loop as FST can antagonize activin A (see below). Description The human FST gene is comprised of six exons spanning 5329 bp on chromosome 5q11.2 and gives Intron/exon structure of the FST gene and domain architecture of FST proteins. 1, 2, 3, 4, 5, 6A, 6B: exon number; SP: signal peptide; NTD: N-terminal domain; FSD: follistatin domain; AT: acidic tail. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1132 FST (follistatin) Grusch M bound activin is unable to initiate signal transduction and consequently follistatin is a potent antagonist of physiological activin signals. Of the three follistatin domains present in all follistatin isoforms, (Shimasaki et al., 1988) the first two, but not the third, are necessary for activin A binding (Keutmann et al., 2004; Harrington et al., 2006). Aside from activins, follistatin also binds several bone morphogenetic proteins (BMP) including BMP2, BMP4, BMP6 and BMP7 (Iemura et al., 1998; Glister et al., 2004). In 2004 it was shown that follistatin binds myostatin (also known as growth and differentiation factor 8, GDF8) with high affinity and thereby is able to antagonize the inhibitory effect of myostatin on muscle growth (Amthor et al., 2004). The functional significance of the interaction between follistatin and angiogenin, a pro-angiogenic factor unrelated to the TGF beta family, remains to be determined (Gao et al., 2007). The interaction of follistatin with heparin and heparan sulfates is isoform specific. Follistatin 288 binds to heparan sulfates, whereas this binding is blocked by the acidic tail of follistatin 315 (Sugino et al., 1993). Knock-out mice for follistatin die within hours after birth and show multiple abnormalities of muscles, skin and skeleton (Matzuk et al., 1995). Evidence from many organs and tissues shows that counterbalancing of signals from TGF beta family members by follistatin is crucial for normal tissue development, architecture and function (de Kretser et al., 2004; McDowall et al., 2008; Kreidl et al., 2009; Antsiferova et al., 2009). Due to the capability for efficient antagonization of signals from activin and myostatin, the therapeutic application of follistatin has been discussed in several clinical conditions involving elevated activin/myostatin activity. Potential areas of application include blocking increased activin expression in inflammation (Phillips et al., 2009) and fibrotic disorders (Aoki and Kojima, 2007) and inhibition of myostatin in muscle diseases (Rodino-Klapac et al., 2009). Other factors and pathways that have been demonstrated to stimulate follistatin gene transcription are gonadotropin-releasing hormone (GnRH) acting via cAMP and CREB (Winters et al., 2007), GLI2, a transcription factor activated by hedgehog signaling (Eichberger et al., 2008), dexamethasone (Hayashi et al., 2009), androgens and activators of wnt signaling (Willert et al., 2002; Yao et al., 2004; Singh et al., 2009). Repression of the follistatin promoter in response to peroxisome proliferator-activated receptor gamma was mediated via SP1 (Necela et al., 2008). Protein Description Mature secreted follistatin protein exists in three main forms consisting of 288, 303, and 315 amino acids (Sugino et al., 1993). The FST344 transcript gives rise to a protein precursor of 344 amino acids, which results in the mature 315 amino acid form after removal of the signal peptide. A fraction of follistatin 315 is further converted to the 303 amino acid form by proteolytic cleavage at the C-terminus. Signal peptide removal of FST317 leads to the mature 288 amino acid form of follistatin. All forms of follistatin contain three follistatin domains (FSD) characterized by a conserved arrangement of 10 cysteine residues. The N-terminal subdomains of the FSD have similarity with EGF-like modules, whereas the C-terminal regions resemble the Kazal domains found in multiple serine protease inhibitors. The follistatin protein contains two potential N-glycosilation sites on asparagines 124 and 288. Localisation Follistatin is expressed in a wide variety of tissues and organs with the highest expression in the ovaries and testes (Phillips and de Kretser, 1998; Tortoriello et al., 2001). The signal peptide directs the nascent protein to the secretory pathway and follistatin has been detected in human serum and in cell culture supernatants of multiple cell lines (Phillips and de Kretser, 1998). Among the follistatin isoforms FST315 was secreted faster than FST288 (Schneyer et al., 2003) and due to the lack of binding to cell-surface heparin-sulfated proteoglycans, a larger fraction of FST315 enters the circulation (Schneyer et al., 1996). Homology The follistatin module with its characteristic spacing of cysteines represents a conserved protein domain. Follistatin modules are found in varying numbers in a wider set of secreted proteins including FSTL1, SPARC/osteonectin, or agrin (Ullman and Perkins, 1997). Among these, follistatin-like 3 (FSTL3, FLRG) shares a similar overall domain architecture with follistatin, but harbors only two instead of three follistatin modules (Tortoriello et al., 2001). With respect to activin binding ability, functional homology among follistatin domain-containing proteins is only found between follistatin and FSTL3, whereas all other follistatin family proteins have not been demonstrated to bind proteins of the TGF beta family (Tsuchida et al., 2000). Follistatin is also highly conserved between species with around 97% amino acid identity in human, mouse and rat. Function Follistatin binds to several members of the TGF beta family and blocks the interaction of these cytokines with their cognate receptors. Follistatin was first identified as a factor that could inhibit the release of follicle-stimulating hormone from pituitary cells (Ueno et al., 1987). It binds activins A, B and AB with high affinity and was also reported to bind activin E but not activin C (Nakamura et al., 1990; Schneyer et al., 1994; Hashimoto et al., 2002; Wada et al., 2004). Follistatin- Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1133 FST (follistatin) Grusch M Sugino K, Kurosawa N, Nakamura T, Takio K, Shimasaki S, Ling N, Titani K, Sugino H. Molecular heterogeneity of follistatin, an activin-binding protein. Higher affinity of the carboxyl-terminal truncated forms for heparan sulfate proteoglycans on the ovarian granulosa cell. J Biol Chem. 1993 Jul 25;268(21):15579-87 Implicated in Malignancy Note Overexpression of follistatin has been found in rat and mouse models of hepatocellular carcinoma (HCC) (Rossmanith et al., 2002; Fujiwara et al., 2008) as well as in tumor tissue and serum of HCC patients (Yuen et al., 2002; Grusch et al., 2006; Beale et al., 2008). However, follistatin had no benefit as surveillance biomarker for HCC development in patients with alcoholic and non-alcoholic liver disease (ALD and NAFLD) due to the already elevated levels in the underlying liver pathologies (Beale et al., 2008). Follistatin overexpression was also demonstrated in human melanoma cell lines (Stove et al., 2004) and has been suggested as candidate biomarker for lung cancer (Planque et al., 2009). Schneyer AL, Rzucidlo DA, Sluss PM, Crowley WF Jr. Characterization of unique binding kinetics of follistatin and activin or inhibin in serum. Endocrinology. 1994 Aug;135(2):667-74 Matzuk MM, Lu N, Vogel H, Sellheyer K, Roop DR, Bradley A. Multiple defects and perinatal death in mice deficient in follistatin. Nature. 1995 Mar 23;374(6520):360-3 Schneyer AL, Hall HA, Lambert-Messerlian G, Wang QF, Sluss P, Crowley WF Jr. Follistatin-activin complexes in human serum and follicular fluid differ immunologically and biochemically. Endocrinology. 1996 Jan;137(1):240-7 Ullman CG, Perkins SJ. The Factor I and follistatin domain families: the return of a prodigal son. Biochem J. 1997 Sep 15;326 ( Pt 3):939-41 Iemura S, Yamamoto TS, Takagi C, Uchiyama H, Natsume T, Shimasaki S, Sugino H, Ueno N. Direct binding of follistatin to a complex of bone-morphogenetic protein and its receptor inhibits ventral and epidermal cell fates in early Xenopus embryo. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9337-42 Endometriosis Note Follistatin was increased in serum of women with ovarian endometriosis and suggested as biomarker for endometrioma (Florio et al., 2009). Phillips DJ, de Kretser DM. Follistatin: a multifunctional regulatory protein. Front Neuroendocrinol. 1998 Oct;19(4):287322 Polycystic ovary syndrome Urbanek M, et al. Thirty-seven candidate genes for polycystic ovary syndrome: strongest evidence for linkage is with follistatin. Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8573-8 Note A genetic linkage analysis found evidence for linkage of follistatin with polycystic ovary syndrome (PCOS) (Urbanek et al., 1999). Another study reported that the follistatin gene is not a susceptibility locus for PCOS but a single nucleotide polymorphism of the gene may be involved in the hyperandrogenaemia of the disease (Jones et al., 2007). Tsuchida K, Arai KY, Kuramoto Y, Yamakawa N, Hasegawa Y, Sugino H. Identification and characterization of a novel follistatin-like protein as a binding protein for the TGF-beta family. J Biol Chem. 2000 Dec 29;275(52):40788-96 Tortoriello DV, Sidis Y, Holtzman DA, Holmes WE, Schneyer AL. Human follistatin-related protein: a structural homologue of follistatin with nuclear localization. Endocrinology. 2001 Aug;142(8):3426-34 Liver failure Note Serum levels of follistatin and activin A were increased in patients with acute liver failure and it was suggested that a decreased follistatin/activin A ratio in the blood may be an indicator for the severity of liver injury in hepatitis-related acute liver disease (Hughes and Evans, 2003; Lin et al., 2006). 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Transcriptional regulation of follistatin expression by GnRH in mouse gonadotroph cell lines: evidence for a role for cAMP signaling. Mol Cell Endocrinol. 2007 Jun 15;271(1-2):45-54 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Grusch M. FST (follistatin). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1132-1135. 1135 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review GATA6 (GATA binding protein 6) Rosalyn M Adam, Joshua R Mauney Urological Diseases Research Center, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA (RMA, JRM) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/GATA6ID40690ch18q11.html DOI: 10.4267/2042/44915 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology family members. The non-coding exons possess regulatory capability and may act to promote transcription. Two isoforms of GATA6 are expressed from two distinct open reading frames and distinct initiator Met codons as a result of leaky ribosome scanning. There are no apparent differences in the amounts or sites of expression of the two transcripts that result from initiation at different Met codons. Identity Other names: GATA-6 HGNC (Hugo): GATA6 Location: 18q11.2 Local order: GATA-6 is flanked in the direction of the centromere by: LOC100128893, hypothetical protein LOC100128893 RNU7-17P, RNA U7 small nuclear 17 pseudogene LOC100287318 - RPL34P32, ribosomal protein L34 pseudogene 32 - MIB1, mindbomb homolog 1 - MIR12 - MIR133A1. GATA6 is flanked in the direction of the telomere by: CTAGE1, cutaneous T-cell lymphoma-associated antigen 1 - RPS4P18, ribosomal protein S4X pseudogene 18 - RBBP8, retinoblastoma binding protein 8 - CABLES1, Cdk5 and Abl enzyme substrate 1 - C18orf45, chromosome 18 open reading frame 45 RIOK3, RIO kinase 3. Note: GATA6 is one of a family of 6 related GATA binding proteins. All six proteins possess zinc fingertype DNA binding domains and act as transcription factors. Protein Description The GATA6 protein products that result from different initiation codons comprise a long isoform of 595 aa (64 kDa) and a short isoform of 449 aa (52 kDa). Both isoforms possess an N-terminal transactivation domain and two zinc finger domains, all of which are essential for activity (Takeda et al., 2004). The two isoforms display different transactivation potential on GATA6-dependent promoters with long GATA6 showing higher activity than short GATA6. Expression GATA6 is expressed predominantly in tissues of mesodermal and endodermal origin. In early development, high levels are detected in the precardiac mesoderm, embryonic heart tube and primitive gut. As development proceeds GATA6 expression is observed in vascular smooth muscle cells, the developing airways, urogenital ridge and bladder (Morrisey et al., 1996). DNA/RNA Description Genomic DNA encoding GATA6 encompasses 33088 bp on the long arm of chromosome 18. The gene is encoded on the plus (forward) strand. Transcription Localisation The pre-mRNA comprises 7 exons, one of which is non-coding, and 6 introns. The mouse and human GATA6 genes contain two alternative non-coding upstream exons, transcribed from two distinct promoters (Brewer et al., 1999), similar to other GATA Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Nuclear. Function GATA6 binds to a 5'-(T/A)GATA(A/G)-3' consensus sequence in the promoters of target genes to regulate 1136 GATA6 (GATA binding protein 6) Adam RM, Mauney JR their transcription. GATA6 is post-translationallly modified by MEK/Erk-dependent phosphorylation at Ser120 (S266 in long GATA6). Ser120Ala mutation abolished GATA6 DNA-binding activity and GATA6mediated Nox1 promoter activation, and also suppressed growth of CaCo-2 colon carcinoma cells (Adachi et al., 2008). GATA6 activity is also regulated through interaction with members of the Friend of GATA (FOG) family of proteins. Two FOG proteins have been identified in mice and humans, FOG-1 and FOG-2, and their interaction with GATA factors can promote or inhibit GATA activity, depending on context (Cantor and Orkin, 2005). GATA6 is essential for normal development, since genetic knockout in mice leads to embryonic lethality as early as E6.5. The underlying defect in GATA6-null mice was determined to be a failure of endoderm differentiation resulting in attenuated expression of GATA6 target genes including GATA4, HNF3beta and HNF4 (Morrisey et al., 1998). GATA6 was shown subsequently to be essential for early extraembryonic development (Koutsourakis et al., 1999). Partial rescue of GATA6-deficient embryos by tetraploid embryo complementation demonstrated additional functions for GATA6 in liver development. The early lethality in GATA6-null embryos could be overcome by providing wild type extraembryonic endoderm and allowed embryos to proceed through gastrulation. However, although hepatic specification occurred normally in rescued GATA6-/- embryos, normal differentiation did not occur and hepatic development arrested at E10.5 (Zhao et al., 2005). Early development of other organ systems was unaffected in rescued GATA6-null embryos, including the heart and vasculature. Interestingly, conditional deletion of GATA6 using SM22alpha promoter-driven Cre recombinase led to perinatal lethality as a result of cardiovascular defects emerging later in embryonic development. In that analysis, the underlying mechanism was determined to be diminished expression of the vascular and neuronal guidance molecule semaphorin 3C, a direct target of GATA6 (Lepore et al., 2006). Consistent with GATA6dependent regulation of Sema3C in mice, mutations in GATA6 were found to cause cardiac outflow tract defects in humans by dysregulating semaphorindependent signaling (Kodo et al., 2009). In general, GATA6 does not act alone in regulating developmental processes, but rather achieves its effects through physical and functional interaction with other transcription factors and signaling molecules, including FOG factors, GATA4 (Xin et al., 2006; Zhao et al., 2008), Tbx5 (Maitra et al., 2009), members of the Nkx2 family (Peterkin et al., 2003) and Wnt family proteins. The complexity of these interactions is exemplified by the functional cooperation of Wnt2 and GATA6 in regulating heart development. In this case, GATA6 not only regulates Wnt2 transcription during Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) heart development through direct binding to the Wnt2 promoter (Alexandrovich et al., 2006), but is itself regulated by a Wnt2-dependent mechanism, since GATA6 expression is markedly reduced in Wnt2-null mice (Tian et al., 2010). GATA6 has also been implicated in regulating development of other organs including the lung and pancreas. In the lung, GATA6 has been shown to regulate specification, differentiation and maturation of the pulmonary epithelium as well as branching morphogenesis (Keijzer et al., 2001; Yang et al., 2002; Liu et al., 2002; Zhang et al., 2008). Inhibition of GATA6 at E6.0 prevented alveolar maturation and also diminished expression of surfactant proteins required for normal pulmonary function. In the pancreas, GATA6 is co-expressed with GATA4 in the epithelium early in development, but as development progresses is expressed only in endocrine cells. Ablation of GATA6 function using a dominant inhibitory engrailed fusion protein strategy led to a reduction or complete loss of pancreatic tissue, consistent with a critical role for GATA6 in pancreatic development (Decker et al., 2006). GATA6 has also been implicated in postnatal maintenance of the differentiated phenotype in various tissues including bladder smooth muscle (Kanematsu, 2007), gut mucosa (Fang, 2006) and airway epithelium (Zhang, 2008). Homology GATA6 shares homology with the other 5 GATA factors, all of which are evolutionarily conserved across multiple species. All 6 GATA factors possess two zinc fingers of the Cys-X2-Cys-X17-Cys-X2-Cys configuration. The C-terminal zinc finger mediates high affinity DNA binding and the N-terminal zinc finger stabilizes the interaction with DNA. Mutations Germinal None known. Somatic Two mutations in GATA6 were identified in patients with persistent truncus arteriosus, as follows (Kodo et al., 2009). GATA6-E486del resulted in conversion of P489 to a stop codon, disruption of the nuclear localization signal and truncation of the C-terminus by 100 aa. The encoded protein showed abnormal nuclear localization, no transcriptional activity against atrial natriuretic factor and WNT2 promoters and was dominant negative. GATA6-N466H contained a point mutation in the Cterminal zinc finger domain. Despite normal nuclear localization, the encoded protein had no transcriptional activity against atrial natriuretic factor and WNT2 promoters. 1137 GATA6 (GATA binding protein 6) Adam RM, Mauney JR histone deacetylase activity with trichostatin A restored GATA6 and GATA4 expression in cell lines (Caslini et al., 2006). Prognosis Loss of GATA6 expression precedes neoplastic transformation in ovarian surface epithelia (Cai et al., 2009) and is correlated with loss of markers of differentiated epithelia (Capo-chichi et al., 2003). Although a majority of ovarian carcinomas retained GATA4 expression, most had either aberrantly localized or absent GATA6 expression. Cytoplasmic expression of GATA6 showed a correlation with overall survival, but this association did not reach statistical significance (McEachin, 2008). Implicated in Pancreatic cancer, pancreatobiliary cancer Disease Genomic profiling of pancreatic and bile duct cancers revealed focal amplification at 18q11.2 that encoded GATA6. Amplification led to overexpression of GATA6 at both mRNA and protein levels in nearly 50% of tumor samples, whereas no normal pancreatic tissues showed overexpression (Kwei et al., 2008; Fu et al., 2008). Consistent with an oncogenic role for GATA6 in pancreatic cancer, RNAi-mediated silencing in pancreatic cancer cell lines in which GATA6 was amplified decreased cell cycle transit, growth and clonogenic ability (Kwei et al., 2008). Conversely forced expression of GATA6 in a pancreatic cancer cell line stimulated anchorage-independent growth and proliferation (Fu et al., 2008). Prognosis GATA6 silencing by RNAi in pancreatic cancer cells in vitro reduced proliferation, cell cycle transit and colony formation, whereas forced overexpression promoted colony formation in soft agar and enhanced proliferation, consistent with a role for GATA6 in driving the tumorigenic phenotype. Cytogenetics Focal amplification of the locus encoding GATA6 at 18q11.2 was identified by array-based genomic profiling and validated by fluorescence in situ hybridization, quantitative PCR, immunohistochemical analysis and immunoblotting. Gastrointestinal cancer Disease Expression of GATA6 has been linked, both positively and negatively, to development of gastrointestinal tract tumors. Prognosis GATA6 expression was found to be decreased in colon carcinoma compared to normal intestinal tissue or benign intestinal lesions (Haveri et al., 2008), which showed robust expression, especially in cells with proliferative capacity. Conversely GATA6 was reported to be overexpressed in human colon cancer cells, where it contributes to silencing of 15lipoxygenase-1 (Shureiqi et al., 2007). The biological significance of this discrepancy in GATA6 expression between colon cancer cells and tissues has not been determined. Expression profiling of Barrett's esophagus and adenocarcinoma to identify genes whose expression correlated with disease progression revealed changes in GATA6 expression among other genes, consistent with upregulation of GATA6 in the transition from normal esophageal epithelium to carcinoma (Kimchi et al., 2005). Ovarian cancer Disease Consistent with their expression in the mouse ovary, GATA6, GATA4 and FOG2 are also expressed in human ovary and in tumors derived from granulosa and thecal cells (Laitinen, 2000). Under normal conditions, both GATA4 and GATA6 are robustly expressed in ovarian surface epithelial cells. However, in a majority of ovarian carcinomas, GATA6 is lost or mislocalized to the cytoplasm (Capo-chichi et al., 2003; McEachin et al., 2008), leading to irreversible epithelial dedifferentiation (Capo-chichi et al., 2003). Expression of GATA4 and GATA6 was shown to correlate with specific histological subtypes of ovarian cancer. In particular, although expression of both factors was lost in the over 80% of endometrioid, clear cell and serous tumors, GATA4 and GATA6 expression persisted in mucinous carcinomas (Cai et al., 2009). Loss of GATA factor expression preceded neoplastic transformation, consistent with an important role for these proteins in tumor development. The mechanism underlying loss of GATA6 and GATA4 expression in ovarian cancer cell lines was demonstrated to be histone deacetylation at the GATA factor promoter regions. Inhibition of Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Lung cancer Disease Despite substantial evidence linking GATA6 to pulmonary development, only one study has investigated the potential role of GATA6 in lung cancer. Specifically, expression of GATA6 was evaluated in malignant mesothelioma and pleural metastases of lung adenocarcinomas and staining patterns correlated with biological and clinical outcomes. Nuclear immunoreactivity for GATA-6 was stronger and more frequent in malignant mesothelioma than in metastatic lung adenocarcinoma (Lindholm et al., 2009). However, no relationship was found between GATA6 expression and growth or apoptotic endpoints. Prognosis Prognosis was better in malignant mesothelioma patients whose tumors expressed GATA-6 compared to 1138 GATA6 (GATA binding protein 6) Adam RM, Mauney JR those whose tumors had no GATA-6 expression, and the relationship was highly statistically significant. Reciprocal changes in the expression of transcription factors GATA-4 and GATA-6 accompany adrenocortical tumorigenesis in mice and humans. Mol Med. 1999 Jul;5(7):490-501 Adrenocortical cancer Koutsourakis M, Langeveld A, Patient R, Beddington R, Grosveld F. The transcription factor GATA6 is essential for early extraembryonic development. Development. 1999 May;126(9):723-32 Disease GATA6 has been implicated in development of the normal adrenal gland. GATA6 mRNA, although expressed in the normal adrenal cortex was found to be absent from experimental mouse adrenocortical tumors, whereas GATA-4 showed the opposite pattern (Kiiveri, 1999; Rahman et al., 2001). GATA-6 expression was also decreased in human adrenocortical carcinomas compared to normal adrenal tissue and adenomas (Kiiveri et al., 2004). The physiologic relevance of altered GATA6 expression in adrenocortical tumorigenesis has not yet been elucidated. However, based on expression of the CDK inhibitor p21 and proliferation marker Ki67, GATA-6 expression in adrenocortical tumors does not appear to be linked to regulation of cell proliferation. Prognosis The prognostic significance of GATA-6 in adrenocortical tumors has not been determined. Laitinen MP, Anttonen M, Ketola I, Wilson DB, Ritvos O, Butzow R, Heikinheimo M. Transcription factors GATA-4 and GATA-6 and a GATA family cofactor, FOG-2, are expressed in human ovary and sex cord-derived ovarian tumors. J Clin Endocrinol Metab. 2000 Sep;85(9):3476-83 Keijzer R, van Tuyl M, Meijers C, Post M, Tibboel D, Grosveld F, Koutsourakis M. The transcription factor GATA6 is essential for branching morphogenesis and epithelial cell differentiation during fetal pulmonary development. Development. 2001 Feb;128(4):503-11 Rahman NA, Kiiveri S, Siltanen S, Levallet J, Kero J, Lensu T, Wilson DB, Heikinheimo MT, Huhtaniemi IT. Adrenocortical tumorigenesis in transgenic mice: the role of luteinizing hormone receptor and transcription factors GATA-4 and GATA-61. Reprod Biol. 2001 Jul;1(1):5-9 Liu C, Morrisey EE, Whitsett JA. GATA-6 is required for maturation of the lung in late gestation. Am J Physiol Lung Cell Mol Physiol. 2002 Aug;283(2):L468-75 Yang H, Lu MM, Zhang L, Whitsett JA, Morrisey EE. GATA6 regulates differentiation of distal lung epithelium. Development. 2002 May;129(9):2233-46 Germ cell tumors Disease Germ cell tumors comprise a heterogeneous group of lesions, including teratomas, yolk sac tumors and embryonal carcinoma. Using in situ hybridization and immunohistochemical staining, GATA6 was evaluated in pediatric germ cell tumors and was found to be expressed in a majority of yolk sac tumors. GATA6 expression was also evident in distinct cell types comprising teratomas, including gut and airway epithelia (Siltanen et al., 2003), but was variable in carcinoma in situ of the testis and absent from embryonal carcinomas and choriocarcinomas (Salonen et al., 2010). Prognosis The prognostic role of GATA6 in germ cell tumors is unknown. Capo-chichi CD, Roland IH, Vanderveer L, Bao R, Yamagata T, Hirai H, Cohen C, Hamilton TC, Godwin AK, Xu XX. Anomalous expression of epithelial differentiation-determining GATA factors in ovarian tumorigenesis. Cancer Res. 2003 Aug 15;63(16):4967-77 Peterkin T, Gibson A, Patient R. GATA-6 maintains BMP-4 and Nkx2 expression during cardiomyocyte precursor maturation. EMBO J. 2003 Aug 15;22(16):4260-73 Siltanen S, Heikkilä P, Bielinska M, Wilson DB, Heikinheimo M. Transcription factor GATA-6 is expressed in malignant endoderm of pediatric yolk sac tumors and in teratomas. Pediatr Res. 2003 Oct;54(4):542-6 Takeda M, Obayashi K, Kobayashi A, Maeda M. A unique role of an amino terminal 16-residue region of long-type GATA-6. J Biochem. 2004 May;135(5):639-50 Cantor AB, Orkin SH. Coregulation of GATA factors by the Friend of GATA (FOG) family of multitype zinc finger proteins. Semin Cell Dev Biol. 2005 Feb;16(1):117-28 References Kiiveri S, Liu J, Arola J, Heikkilä P, Kuulasmaa T, Lehtonen E, Voutilainen R, Heikinheimo M. Transcription factors GATA-6, SF-1, and cell proliferation in human adrenocortical tumors. Mol Cell Endocrinol. 2005 Apr 15;233(1-2):47-56 Morrisey EE, Ip HS, Lu MM, Parmacek MS. GATA-6: a zinc finger transcription factor that is expressed in multiple cell lineages derived from lateral mesoderm. Dev Biol. 1996 Jul 10;177(1):309-22 Kimchi ET, Posner MC, Park JO, Darga TE, Kocherginsky M, Karrison T, Hart J, Smith KD, Mezhir JJ, Weichselbaum RR, Khodarev NN. Progression of Barrett's metaplasia to adenocarcinoma is associated with the suppression of the transcriptional programs of epidermal differentiation. Cancer Res. 2005 Apr 15;65(8):3146-54 Morrisey EE, Tang Z, Sigrist K, Lu MM, Jiang F, Ip HS, Parmacek MS. GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. Genes Dev. 1998 Nov 15;12(22):3579-90 Brewer A, Gove C, Davies A, McNulty C, Barrow D, Koutsourakis M, Farzaneh F, Pizzey J, Bomford A, Patient R. The human and mouse GATA-6 genes utilize two promoters and two initiation codons. J Biol Chem. 1999 Dec 31;274(53):38004-16 Zhao R, Watt AJ, Li J, Luebke-Wheeler J, Morrisey EE, Duncan SA. GATA6 is essential for embryonic development of the liver but dispensable for early heart formation. Mol Cell Biol. 2005 Apr;25(7):2622-31 Kiiveri S, Siltanen S, Rahman N, Bielinska M, Lehto VP, Huhtaniemi IT, Muglia LJ, Wilson DB, Heikinheimo M. Alexandrovich A, Arno M, Patient RK, Shah AM, Pizzey JA, Brewer AC. Wnt2 is a direct downstream target of GATA6 during early cardiogenesis. Mech Dev. 2006 Apr;123(4):297311 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1139 GATA6 (GATA binding protein 6) Adam RM, Mauney JR Caslini C, Capo-chichi CD, Roland IH, Nicolas E, Yeung AT, Xu XX. Histone modifications silence the GATA transcription factor genes in ovarian cancer. Oncogene. 2006 Aug 31;25(39):5446-61 McEachin MD, Xu XX, Santoianni RA, Lawson D, Cotsonis G, Cohen C. GATA-4 and GATA-6 expression in human ovarian surface epithelial carcinoma. Appl Immunohistochem Mol Morphol. 2008 Mar;16(2):153-8 Decker K, Goldman DC, Grasch CL, Sussel L. Gata6 is an important regulator of mouse pancreas development. Dev Biol. 2006 Oct 15;298(2):415-29 Zhang Y, Goss AM, Cohen ED, Kadzik R, Lepore JJ, Muthukumaraswamy K, Yang J, DeMayo FJ, Whitsett JA, Parmacek MS, Morrisey EE. A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration. Nat Genet. 2008 Jul;40(7):862-70 Fang R, Olds LC, Sibley E. Spatio-temporal patterns of intestine-specific transcription factor expression during postnatal mouse gut development. Gene Expr Patterns. 2006 Apr;6(4):426-32 Zhao R, Watt AJ, Battle MA, Li J, Bondow BJ, Duncan SA. Loss of both GATA4 and GATA6 blocks cardiac myocyte differentiation and results in acardia in mice. Dev Biol. 2008 May 15;317(2):614-9 Lepore JJ, Mericko PA, Cheng L, Lu MM, Morrisey EE, Parmacek MS. GATA-6 regulates semaphorin 3C and is required in cardiac neural crest for cardiovascular morphogenesis. J Clin Invest. 2006 Apr;116(4):929-39 Cai KQ, Caslini C, Capo-chichi CD, Slater C, Smith ER, Wu H, Klein-Szanto AJ, Godwin AK, Xu XX. Loss of GATA4 and GATA6 expression specifies ovarian cancer histological subtypes and precedes neoplastic transformation of ovarian surface epithelia. PLoS One. 2009 Jul 31;4(7):e6454 Xin M, Davis CA, Molkentin JD, Lien CL, Duncan SA, Richardson JA, Olson EN. A threshold of GATA4 and GATA6 expression is required for cardiovascular development. Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11189-94 Kodo K, Nishizawa T, Furutani M, Arai S, Yamamura E, Joo K, Takahashi T, Matsuoka R, Yamagishi H. GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling. Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13933-8 Kanematsu A, Ramachandran A, Adam RM. GATA-6 mediates human bladder smooth muscle differentiation: involvement of a novel enhancer element in regulating alpha-smooth muscle actin gene expression. Am J Physiol Cell Physiol. 2007 Sep;293(3):C1093-102 Lindholm PM, Soini Y, Myllärniemi M, Knuutila S, Heikinheimo M, Kinnula VL, Salmenkivi K. Expression of GATA-6 transcription factor in pleural malignant mesothelioma and metastatic pulmonary adenocarcinoma. J Clin Pathol. 2009 Apr;62(4):339-44 Shureiqi I, Zuo X, Broaddus R, Wu Y, Guan B, Morris JS, Lippman SM. The transcription factor GATA-6 is overexpressed in vivo and contributes to silencing 15-LOX-1 in vitro in human colon cancer. FASEB J. 2007 Mar;21(3):743-53 Maitra M, Schluterman MK, Nichols HA, Richardson JA, Lo CW, Srivastava D, Garg V. Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development. Dev Biol. 2009 Feb 15;326(2):368-77 Adachi Y, Shibai Y, Mitsushita J, Shang WH, Hirose K, Kamata T. Oncogenic Ras upregulates NADPH oxidase 1 gene expression through MEK-ERK-dependent phosphorylation of GATA-6. Oncogene. 2008 Aug 21;27(36):4921-32 Salonen J, Rajpert-De Meyts E, Mannisto S, Nielsen JE, Graem N, Toppari J, Heikinheimo M. Differential developmental expression of transcription factors GATA-4 and GATA-6, their cofactor FOG-2 and downstream target genes in testicular carcinoma in situ and germ cell tumors. Eur J Endocrinol. 2010 Mar;162(3):625-31 Fu B, Luo M, Lakkur S, Lucito R, Iacobuzio-Donahue CA. Frequent genomic copy number gain and overexpression of GATA-6 in pancreatic carcinoma. Cancer Biol Ther. 2008 Oct;7(10):1593-601 Haveri H, Westerholm-Ormio M, Lindfors K, Mäki M, Savilahti E, Andersson LC, Heikinheimo M. Transcription factors GATA4 and GATA-6 in normal and neoplastic human gastrointestinal mucosa. BMC Gastroenterol. 2008 Apr 11;8:9 Tian Y, Yuan L, Goss AM, Wang T, Yang J, Lepore JJ, D, Schwartz RJ, Patel V, Cohen ED, Morrisey Characterization and in vivo pharmacological rescue Wnt2-Gata6 pathway required for cardiac inflow development. Dev Cell. 2010 Feb 16;18(2):275-87 Kwei KA, Bashyam MD, Kao J, Ratheesh R, Reddy EC, Kim YH, Montgomery K, Giacomini CP, Choi YL, Chatterjee S, Karikari CA, Salari K, Wang P, Hernandez-Boussard T, Swarnalata G, van de Rijn M, Maitra A, Pollack JR. Genomic profiling identifies GATA6 as a candidate oncogene amplified in pancreatobiliary cancer. PLoS Genet. 2008 May 23;4(5):e1000081 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Zhou EE. of a tract This article should be referenced as such: Adam RM, Mauney JR. GATA6 (GATA binding protein 6). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):11361140. 1140 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review HIPK2 (homeodomain interacting protein kinase 2) Dirk Sombroek, Thomas G Hofmann Deutsches Krebsforschungszentrum (dkfz.), Cellular Senescence Unit A210, Cell and Tumor Biology Program, Heidelberg, Germany (DS, TGH) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/HIPK2ID40824ch7q34.html DOI: 10.4267/2042/44916 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity HIPK2-202 [ENST00000342645]; 2757 bp linear mRNA; 918 amino acids. Other names: DKFZp686K02111, FLJ23711, hHIPk2, PRO0593 HGNC (Hugo): HIPK2 Location: 7q34 Pseudogene DNA/RNA Description Nothing known. Protein HIPK2 is a protein kinase of 1198 amino acids (131 kDa); posttranslational modifications: phosphorylation, ubiquitination, sumoylation at K25, caspase cleavage at D916 and D977. Contains several motifs and domains (from N- to Cterminus): a nuclear localisation signal (NLS)1 (97157), a kinase domain (192-520), an interaction domain for homeodomain transcription factors (583-798), a NLS2 (780-840) and a NLS3 within a speckle-retention signal (SRS) (860-967), a PEST sequence (839-934) and an autoinhibitory domain (935-1050). Description Zhang et al. (2005) reported 13 exons that span around 60 kb; however, up to 15 exons are listed in different databases. Transcription Around 15 kb mRNA (full-length); 3594 bp open reading frame. At least two alternative transcripts. Entrez Nucleotide: [NM_022740.4] Homo sapiens HIPK2, transcript variant 1; 15245 bp linear mRNA; full-length isoform, [NM_001113239.2] Homo sapiens HIPK2, transcript variant 2; 15164 bp linear mRNA; this variant lacks an internal segment in the CDS, the resulting isoform is shorter. UniProtHB/Swiss-Prot [Q9H2X6]: [Q9H2X6-1] full-length isoform (1), [Q9H2X6-2] isoform (2), [Q9H2X6-3] isoform (3). Ensemble Gene [ENSG00000064393]; 4 transcripts: HIPK2-001 [ENST00000406875]; 15049 bp linear mRNA; 1198 amino acids, Expression HIPK2 is ubiquitously expressed (high mRNA levels in neuronal tissues, heart, muscle and kidney); but barely detectable at protein levels in unstressed cells. Protein levels increase upon genotoxic stress. Localisation Mainly nuclear localisation, in nuclear bodies; but also found in nucleoplasm and cytoplasm. Function HIPK2 is a potential tumour suppressor; in vivo data suggest at least a role as an haploinsufficient tumour suppressor in the skin of mice. HIPK2 is a protein kinase that interacts with numerous transcription factors (such as p53, AML1(RUNX1), PAX6, c-MYB or NK3) as well as transcriptional HIPK2-002 [ENST00000428878]; 3969 bp linear mRNA; 1171 amino acids, HIPK2-201 [ENST00000263551]; 14953 bp linear mRNA; 1198 amino acids, Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1141 HIPK2 (homeodomain interacting protein kinase 2) Sombroek D, Hofmann TG regulators (such as CBP, p300, Groucho, CtBP, HMGA1 or Smads). In this way HIPK2 can activate or repress transcription and thereby influence differentiation, development and the DNA damage response. HIPK2 is an unstable protein in unstressed cells. It is constantly degraded via the ubiquitin-proteasome system (mediated by the E3 ubiquitin ligases SIAH1/SIAH2, WSB1 and MDM2). Various types of DNA damage (e.g. UV, IR or chemotherapeutics) lead to stabilisation of the kinase and an HIPK2-mediated induction of apoptosis or presumably also senescence. HIPK2 can promote the apoptotic program via p53dependent and -independent pathways through phosphorylation of p53 at Ser46 or phosphorylation of the anti-apoptotic co-repressor CtBP at Ser422 (both actions leading to the transcription of pro-apoptotic target genes). HIPK2 plays a role in the transcriptional regulation at low oxigen concentrations (hypoxia). Interestingly, HIPK2 also seems to have pro-survival functions, at least in dopamine neurons. Epithelial tumours (with altered beta4 integrin expression) Oncogenesis HIPK2 was reported to repress beta4 integrin expression and thereby beta4-mediated tumour progression in a p53-dependent manner. Beta4 overexpression correlates in vivo with a cytoplasmic relocalisation of HIPK2, at least in breast cancer: HIPK2 showed a cytoplasmic pattern in 62.5% of the beta4-positive tumours (Bon et al., 2009). Juvenile pilocytic astrocytomas (JPA) Note Benign childhood brain tumors. Disease A frequent amplification of HIPK2 along with BRAF rearrangements in JPA (35 out of 53 cases) through 7q34 duplication was reported. This duplication was more specific for JPA that originated from the cerebellum or the optic chiasm. It was absent in other brain tumours. If (and how) HIPK2 contributes to JPA development is currently unclear (Jacob et al., 2009). Homology Cervical cancer HIPK2 is conserved from flies to man. Note Surprisingly, a significant overexpression of HIPK2 in cervical cancer was reported. But if (and how) HIPK2 contributes to the development of cervical carcinomas remains unclear. No correlation between HIPK2 expression and grade or prognosis of the disease could be demonstrated so far (Al-Beiti et al., 2008). Mutations Somatic HIPK2 is rarely mutated (2 out of 130 cases) in acute myeloid leukemia (AML) and myelodyplastic syndrome (MDS) patients. Two missense mutations (R868W and N958I) within the speckle-retention signal (SRS) were reported. These mutations led to a changed nuclear localisation of HIPK2 and a decreased transactivation potential in AML1- and p53-dependent transcription. The mutants showed dominant-negative effects (Li et al., 2007). AML(RUNX1)-associated leukemias Oncogenesis HIPK2 is inactivated on protein level by relocalisation through a PEBP2-beta-SMMHC fusion protein. Targeting of HIPK2 to cytoplasmic filaments and thereby prevention of AML1(RUNX1) activation was reported. Specifically, phosphorylation of RUNX1 and its cofactor p300 seems to be inhibited by HIPK2 relocalisation (Wee et al., 2008). Implicated in Thyroid and breast cancer Oncogenesis HIPK2 is frequently inactivated by transcriptional downregulation in thyroid carcinomas (8 out of 14 cases) and breast carcinomas (8 out of 20 cases) (Pierantoni et al., 2002). References Kim YH, Choi CY, Lee SJ, Conti MA, Kim Y. Homeodomaininteracting protein kinases, a novel family of co-repressors for homeodomain transcription factors. J Biol Chem. 1998 Oct 2;273(40):25875-9 Breast cancer Choi CY, Kim YH, Kwon HJ, Kim Y. The homeodomain protein NK-3 recruits Groucho and a histone deacetylase complex to repress transcription. J Biol Chem. 1999 Nov 19;274(47):33194-7 Oncogenesis HIPK2 is inactivated on protein level by cytoplasmic relocalisation through HMGA1. Overexpression of HMGA1 was reported to inhibit p53-mediated apoptosis by removing HIPK2 from the nucleus and retaining it in the cytoplasm. Observations could be correlated with in vivo data, at least in breast cancer. WT p53-expressing breast carcinomas showed a low spontaneous apoptotic index in case of HIPK2relocalisation (Pierantoni et al., 2007). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Kim YH, Choi CY, Kim Y. Covalent modification of the homeodomain-interacting protein kinase 2 (HIPK2) by the ubiquitin-like protein SUMO-1. Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12350-5 Hofmann TG, Mincheva A, Lichter P, Dröge W, Schmitz ML. Human homeodomain-interacting protein kinase-2 (HIPK2) is a member of the DYRK family of protein kinases and maps to chromosome 7q32-q34. Biochimie. 2000 Dec;82(12):1123-7 1142 HIPK2 (homeodomain interacting protein kinase 2) Sombroek D, Hofmann TG Pierantoni GM, Fedele M, Pentimalli F, Benvenuto G, Pero R, Viglietto G, Santoro M, Chiariotti L, Fusco A. High mobility group I (Y) proteins bind HIPK2, a serine-threonine kinase protein which inhibits cell growth. Oncogene. 2001 Sep 27;20(43):6132-41 Gresko E, Roscic A, Ritterhoff S, Vichalkovski A, del Sal G, Schmitz ML. Autoregulatory control of the p53 response by caspase-mediated processing of HIPK2. EMBO J. 2006 May 3;25(9):1883-94 Isono K, Nemoto K, Li Y, Takada Y, Suzuki R, Katsuki M, Nakagawara A, Koseki H. Overlapping roles for homeodomaininteracting protein kinases hipk1 and hipk2 in the mediation of cell growth in response to morphogenetic and genotoxic signals. Mol Cell Biol. 2006 Apr;26(7):2758-71 Wang Y, Hofmann TG, Runkel L, Haaf T, Schaller H, Debatin K, Hug H. Isolation and characterization of cDNAs for the protein kinase HIPK2. Biochim Biophys Acta. 2001 Mar 19;1518(1-2):168-72 D'Orazi G, Cecchinelli B, Bruno T, Manni I, Higashimoto Y, Saito S, Gostissa M, Coen S, Marchetti A, Del Sal G, Piaggio G, Fanciulli M, Appella E, Soddu S. Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis. Nat Cell Biol. 2002 Jan;4(1):11-9 Kim EA, Noh YT, Ryu MJ, Kim HT, Lee SE, Kim CH, Lee C, Kim YH, Choi CY. Phosphorylation and transactivation of Pax6 by homeodomain-interacting protein kinase 2. J Biol Chem. 2006 Mar 17;281(11):7489-97 Dauth I, Krüger J, Hofmann TG. Homeodomain-interacting protein kinase 2 is the ionizing radiation-activated p53 serine 46 kinase and is regulated by ATM. Cancer Res. 2007 Mar 1;67(5):2274-9 Hofmann TG, Möller A, Sirma H, Zentgraf H, Taya Y, Dröge W, Will H, Schmitz ML. Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. Nat Cell Biol. 2002 Jan;4(1):1-10 Li XL, Arai Y, Harada H, Shima Y, Yoshida H, Rokudai S, Aikawa Y, Kimura A, Kitabayashi I. Mutations of the HIPK2 gene in acute myeloid leukemia and myelodysplastic syndrome impair AML1- and p53-mediated transcription. Oncogene. 2007 Nov 8;26(51):7231-9 Pierantoni GM, Bulfone A, Pentimalli F, Fedele M, Iuliano R, Santoro M, Chiariotti L, Ballabio A, Fusco A. The homeodomain-interacting protein kinase 2 gene is expressed late in embryogenesis and preferentially in retina, muscle, and neural tissues. Biochem Biophys Res Commun. 2002 Jan 25;290(3):942-7 Pierantoni GM, Rinaldo C, Mottolese M, Di Benedetto A, Esposito F, Soddu S, Fusco A. High-mobility group A1 inhibits p53 by cytoplasmic relocalization of its proapoptotic activator HIPK2. J Clin Invest. 2007 Mar;117(3):693-702 Harada J, Kokura K, Kanei-Ishii C, Nomura T, Khan MM, Kim Y, Ishii S. Requirement of the co-repressor homeodomaininteracting protein kinase 2 for ski-mediated inhibition of bone morphogenetic protein-induced transcriptional activation. J Biol Chem. 2003 Oct 3;278(40):38998-9005 Rinaldo C, Prodosmo A, Mancini F, Iacovelli S, Sacchi A, Moretti F, Soddu S. MDM2-regulated degradation of HIPK2 prevents p53Ser46 phosphorylation and DNA damage-induced apoptosis. Mol Cell. 2007 Mar 9;25(5):739-50 Zhang Q, Yoshimatsu Y, Hildebrand J, Frisch SM, Goodman RH. Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP. Cell. 2003 Oct 17;115(2):177-86 Wei G, Ku S, Ma GK, Saito S, Tang AA, Zhang J, Mao JH, Appella E, Balmain A, Huang EJ. HIPK2 represses betacatenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis. Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13040-5 Di Stefano V, Rinaldo C, Sacchi A, Soddu S, D'Orazi G. Homeodomain-interacting protein kinase-2 activity and p53 phosphorylation are critical events for cisplatin-mediated apoptosis. Exp Cell Res. 2004 Feb 15;293(2):311-20 Zhang J, Pho V, Bonasera SJ, Holtzman J, Tang AT, Hellmuth J, Tang S, Janak PH, Tecott LH, Huang EJ. Essential function of HIPK2 in TGFbeta-dependent survival of midbrain dopamine neurons. Nat Neurosci. 2007 Jan;10(1):77-86 Doxakis E, Huang EJ, Davies AM. Homeodomain-interacting protein kinase-2 regulates apoptosis in developing sensory and sympathetic neurons. Curr Biol. 2004 Oct 5;14(19):1761-5 Al-Beiti MA, Lu X. Expression of HIPK2 in cervical cancer: correlation with clinicopathology and prognosis. Aust N Z J Obstet Gynaecol. 2008 Jun;48(3):329-36 Kanei-Ishii C, Ninomiya-Tsuji J, Tanikawa J, Nomura T, Ishitani T, Kishida S, Kokura K, Kurahashi T, Ichikawa-Iwata E, Kim Y, Matsumoto K, Ishii S. Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK. Genes Dev. 2004 Apr 1;18(7):816-29 Choi DW, Seo YM, Kim EA, Sung KS, Ahn JW, Park SJ, Lee SR, Choi CY. Ubiquitination and degradation of homeodomaininteracting protein kinase 2 by WD40 repeat/SOCS box protein WSB-1. J Biol Chem. 2008 Feb 22;283(8):4682-9 Choi CY, Kim YH, Kim YO, Park SJ, Kim EA, Riemenschneider W, Gajewski K, Schulz RA, Kim Y. Phosphorylation by the DHIPK2 protein kinase modulates the corepressor activity of Groucho. J Biol Chem. 2005 Jun 3;280(22):21427-36 Wee HJ, Voon DC, Bae SC, Ito Y. PEBP2-beta/CBF-betadependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis. Blood. 2008 Nov 1;112(9):3777-87 Gresko E, Möller A, Roscic A, Schmitz ML. Covalent modification of human homeodomain interacting protein kinase 2 by SUMO-1 at lysine 25 affects its stability. Biochem Biophys Res Commun. 2005 Apr 22;329(4):1293-9 Winter M, Sombroek D, Dauth I, Moehlenbrink J, Scheuermann K, Crone J, Hofmann TG. Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. Nat Cell Biol. 2008 Jul;10(7):812-24 Zhang D, Li K, Erickson-Miller CL, Weiss M, Wojchowski DM. DYRK gene structure and erythroid-restricted features of DYRK3 gene expression. Genomics. 2005 Jan;85(1):117-30 Bon G, Di Carlo SE, Folgiero V, Avetrani P, Lazzari C, D'Orazi G, Brizzi MF, Sacchi A, Soddu S, Blandino G, Mottolese M, Falcioni R. Negative regulation of beta4 integrin transcription by homeodomain-interacting protein kinase 2 and p53 impairs tumor progression. Cancer Res. 2009 Jul 15;69(14):5978-86 Aikawa Y, Nguyen LA, Isono K, Takakura N, Tagata Y, Schmitz ML, Koseki H, Kitabayashi I. Roles of HIPK1 and HIPK2 in AML1- and p300-dependent transcription, hematopoiesis and blood vessel formation. EMBO J. 2006 Sep 6;25(17):3955-65 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1143 HIPK2 (homeodomain interacting protein kinase 2) Sombroek D, Hofmann TG Calzado MA, de la Vega L, Möller A, Bowtell DD, Schmitz ML. An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response. Nat Cell Biol. 2009 Jan;11(1):85-91 Nardinocchi L, Puca R, Guidolin D, Belloni AS, Bossi G, Michiels C, Sacchi A, Onisto M, D'Orazi G. Transcriptional regulation of hypoxia-inducible factor 1alpha by HIPK2 suggests a novel mechanism to restrain tumor growth. Biochim Biophys Acta. 2009 Feb;1793(2):368-77 Jacob K, Albrecht S, Sollier C, Faury D, Sader E, Montpetit A, Serre D, Hauser P, Garami M, Bognar L, Hanzely Z, Montes JL, Atkinson J, Farmer JP, Bouffet E, Hawkins C, Tabori U, Jabado N. Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br J Cancer. 2009 Aug 18;101(4):722-33 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) This article should be referenced as such: Sombroek D, Hofmann TG. HIPK2 (homeodomain interacting protein kinase 2). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1141-1144. 1144 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review RAD9A (RAD9 homolog A (S. pombe)) Vivian Chan Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China (VC) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/RAD9AID42031ch11q13.html DOI: 10.4267/2042/44917 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology hRad9 forms ring-shape heterotrimeric complex with hRad1 and hHus1 proteins (9-1-1 complex). All 3 proteins have sequence homology with proliferating cell nuclear antigen (PCNA). The 9-1-1 complex is recruited onto DNA-lesion by RAD17 and ATR triggering checkpoint signaling pathway and acts to repair DNA damage (Volkmer and Karnitz, 1999; Rauen et al., 2000; Zou et al., 2002; Medhurst et al., 2008). Phosphorylation of hRad9 by protein kinase C delta (PKCD) is necessary for the formation of the 9-11 complex (Yoshida et al., 2003). NH2 terminus of hRad9 contains BH3-like domain which binds antiapoptotic proteins BCL2 and Bcl-x2, thereby promoting apoptosis (Komatsu et al., 2000). This interaction of hRad9 to Bcl2 is regulated also by PKCdelta (Yoshida et al., 2003). RAD9, like P53 can regulate P21 at the transcriptional level. Overexpression of hRad was shown to cause an increase in P21 RNA and the encoded protein level in P53-null H1299 cells (Yin et al., 2004). This suggests that hRAD9 and P53 coregulate P21 to direct cell cycle progression. hRAD9 may also modulate transcription of other down-stream target genes. C-terminal region of hRad9 protein acts to transport 91-1 complex into the nucleus (Hirai and Wang, 2002; Sohn and Cho, 2009). Identity Other names: RAD9, hRAD9 HGNC (Hugo): RAD9A Location: 11q13.2 Note: Accession No. NM_004584. DNA/RNA Description 6461 bp, 11 exons. Transcription The transcript length is 1176 bp, full open reading frame cDNA clone, encodes a 391 amino acid, 42520 Da protein (Lieberman et al., 1996). Protein Function The gene product is highly similar to Rad9 protein from S pombe. A cell cycle checkpoint protein with multiple functions for preserving genomic integrity (Ishikawa et al., 2006), such as the regulation of DNA damage response, cell cycle checkpoint, DNA repair, apoptosis, transcriptional regulation, exonuclease activity, ribonucleotide synthesis and embryogenesis. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1145 RAD9A (RAD9 homolog A (S. pombe)) Chan V (Adapted from Ishikawa K et al., Current Genomics.2006:7:477-80). hRad9 and ATM rapidly colocalize to regions containing DNA double-stranded breaks after DNAdamage (Greer et al., 2003; Medhurst et al., 2008) and Atm can phosphorylate Rad9 directly at Ser-272 during ionizing radiation (IR)-induced G1/S checkpoint activation (Chen et al., 2001). The 9-1-1 complex may attract DNA polymerase beta to sites of DNA damage, thus connecting checkpoint and DNA repair (Toueille et al., 2004). Thr-292 of hRad9 is subject to CDC2-dependent phosphorylation in mitosis. Four other hRad9 phosphorylation sites (Ser-277, Ser-328, Ser-336 and Thr-355) are regulated in part by Cdc2 (St Onge et al., 2001; St Onge et al., 2003; Ishikawa et al., 2006). Phosphorylation sites of the C-terminal region of hRad9 are essential for CHK1 activation following hydroxyurea, ionizing radiation and ultraviolet treatment (Roos-Mattjus et al., 2003). Crystal structure of the human Rad9-Hus1-Rad1 complex reveals a single repair enzyme binding site (Doré et al., 2009) and suggests that the C-terminal end of Rad9 protein is involved in the regulation of the complex in DNA binding (Sohn and Cho, 2009). hRad9 possesses 3'-5' exonuclease activity which may contribute to its role in sensing and repairing DNA damage (Bessho and Sancar, 2000). The exact mechanism of this exonucleolytic processing is still unclear. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Implicated in Various cancers Oncogenesis Checkpoint genes are known to be involved in the maintenance of genomic integrity and their aberrant expression can lead to cancer. Paralogue of human HRad9 is called HRad9B. Gene product is structurally related to hRad9 protein (55% similar and 35% identical). HRad9B gene is expressed predominantly in the testis and found in decreased amount in testicular tumours, particularly seminomas (Hopkins et al., 2003). Prostate cancer Oncogenesis Carboxy terminus of hRad9 contains a FXXLF motif which interrupts the androgen-induced interaction between the C and N terminus of androgen receptor (AR), acting as a co-regulator to suppress androgen-AR transactivation in prostrate cancer cells (Wang et al., 2004). This denotes a possible tumour suppressor function of hRad9. Recent study has confirmed that high levels of Rad9 expression is found in prostate cancer cells and the high protein levels in prostate adenocarcinomas were generally associated with more advanced disease (Zhu et al., 2008). Similar to previous findings in breast 1146 RAD9A (RAD9 homolog A (S. pombe)) Chan V cancer (Cheng et al., 2005), the increased expression of Rad9 in prostate cancer cells was in part due to aberrant methylation or gene amplification (Zhu et al., 2008). The study failed to show that the role of Rad9 in prostate tumorigenesis was androgen dependent, since both androgen dependent CWR22 and LNCaP cell lines as well as androgen independent DU145 and PC-3 cell lines were found to contain high levels of Rad9 protein (Zhu et al., 2008). mutations lead to hereditary non-polyposis colorectal cancer (HNPCC) (Avdievich et al., 2008; Peltomäki et al., 2004) and various types of tumours (Avdievich et al., 2008; Hu et al., 2008). However, hRad9's function in MMR is not in the 9-1-1-complex form (He et al., 2008). References Lieberman HB, Hopkins KM, Nass M, Demetrick D, Davey S. A human homolog of the Schizosaccharomyces pombe rad9+ checkpoint control gene. Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13890-5 Lung cancer Oncogenesis Presence of hyperphosphorylated forms of hRad9 has been found in the nuclei of surgically resected primary lung carcinoma cells (Maniwa et al., 2005). No mutation of the hRad9 gene was found in lung cancer cells, but a nonsynonymous single nucleotide polymorphism (SNP), His239Arg was found in 8 out of 50 lung adenocarcinoma patients, suggesting a possible association of this SNP with the development of cancer (Maniwa et al., 2006). St Onge RP, Udell CM, Casselman R, Davey S. The human G2 checkpoint control protein hRAD9 is a nuclear phosphoprotein that forms complexes with hRAD1 and hHUS1. Mol Biol Cell. 1999 Jun;10(6):1985-95 Volkmer E, Karnitz LM. Human homologs of Schizosaccharomyces pombe rad1, hus1, and rad9 form a DNA damage-responsive protein complex. J Biol Chem. 1999 Jan 8;274(2):567-70 Bessho T, Sancar A. Human DNA damage checkpoint protein hRAD9 is a 3' to 5' exonuclease. J Biol Chem. 2000 Mar 17;275(11):7451-4 Breast cancer Oncogenesis Over-expression of hRad9 mRNA was found in breast cancer, which was shown to be correlated with tumour size (p = 0.037) and local recurrence (p = 0.033). Overexpression of Rad9 mRNA was partly due to increase in RAD9 gene amplification and aberrant DNA methylation at a putative Sp 1/3 binding site within the second intron of the RAD9 gene. Promoter assays indicate that the Sp 1/3 site in intron 2 may act as a silencer. Further experiments in silencing Rad9 expression by RNAi inhibit the proliferation of MCF-7 cell line in vitro. These findings suggested that Rad9 is a new oncogene candidate on Ch11q13 with a role in breast cancer progression (Cheng et al., 2005). In contrast to previous findings in testicular tumours, increased hRad9 protein was found in the nuclei of breast cancer cells. These were shown to exist as hyperphosphorylated forms, with molecular weights of 65 and 50 kDa. Since the theoretical molecular weight of hRad9 is 45 kDa (Lindsey-Boltz et al., 2001), these larger forms most likely represent hyperphosphorylated hRad9 and its hRad9-hRad1-hHus1 complex (Chan et al., 2008; St Onge et al., 1999). Localization of hyperphosphorylated forms of hRad in the nucleus of cancer cells is in keeping with its function in ameliorating DNA instability, whereby it inadvertently assists tumour growth. Komatsu K, Miyashita T, Hang H, Hopkins KM, Zheng W, Cuddeback S, Yamada M, Lieberman HB, Wang HG. Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis. Nat Cell Biol. 2000 Jan;2(1):1-6 Rauen M, Burtelow MA, Dufault VM, Karnitz LM. The human checkpoint protein hRad17 interacts with the PCNA-like proteins hRad1, hHus1, and hRad9. J Biol Chem. 2000 Sep 22;275(38):29767-71 Chen MJ, Lin YT, Lieberman HB, Chen G, Lee EY. ATMdependent phosphorylation of human Rad9 is required for ionizing radiation-induced checkpoint activation. J Biol Chem. 2001 May 11;276(19):16580-6 Lindsey-Boltz LA, Bermudez VP, Hurwitz J, Sancar A. Purification and characterization of human DNA damage checkpoint Rad complexes. Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11236-41 St Onge RP, Besley BD, Park M, Casselman R, Davey S. DNA damage-dependent and -independent phosphorylation of the hRad9 checkpoint protein. J Biol Chem. 2001 Nov 9;276(45):41898-905 Hirai I, Wang HG. A role of the C-terminal region of human Rad9 (hRad9) in nuclear transport of the hRad9 checkpoint complex. J Biol Chem. 2002 Jul 12;277(28):25722-7 Zou L, Cortez D, Elledge SJ. Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin. Genes Dev. 2002 Jan 15;16(2):198-208 Greer DA, Besley BD, Kennedy KB, Davey S. hRad9 rapidly binds DNA containing double-strand breaks and is required for damage-dependent topoisomerase II beta binding protein 1 focus formation. Cancer Res. 2003 Aug 15;63(16):4829-35 Colorectal cancer Hopkins KM, Wang X, Berlin A, Hang H, Thaker HM, Lieberman HB. Expression of mammalian paralogues of HRAD9 and Mrad9 checkpoint control genes in normal and cancerous testicular tissue. Cancer Res. 2003 Sep 1;63(17):5291-8 Oncogenesis Rad9 interacts physically within the DNA mismatch repair (MMR) protein MLH1. Disruption of the interaction by a single point mutation in Rad9 leads to significantly reduced mismatch repair activity (He et al., 2008). The Rad9-MHL1 interaction might be a hotspot for mutation in tumour cells. The hMLH1 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Roos-Mattjus P, Hopkins KM, Oestreich AJ, Vroman BT, Johnson KL, Naylor S, Lieberman HB, Karnitz LM. Phosphorylation of human Rad9 is required for genotoxin- 1147 RAD9A (RAD9 homolog A (S. pombe)) Chan V activated checkpoint signaling. J Biol Chem. 2003 Jul 4;278(27):24428-37 Maniwa Y, Yoshimura M, Bermudez VP, Okada K, Kanomata N, Ohbayashi C, Nishimura Y, Hayashi Y, Hurwitz J, Okita Y. His239Arg SNP of HRAD9 is associated with lung adenocarcinoma. Cancer. 2006 Mar 1;106(5):1117-22 St Onge RP, Besley BD, Pelley JL, Davey S. A role for the phosphorylation of hRad9 in checkpoint signaling. J Biol Chem. 2003 Jul 18;278(29):26620-8 Yoshida K, Wang HG, Miki Y, Kufe D. Protein kinase Cdelta is responsible for constitutive and DNA damage-induced phosphorylation of Rad9. EMBO J. 2003 Mar 17;22(6):1431-41 Avdievich E, Reiss C, Scherer SJ, Zhang Y, Maier SM, Jin B, Hou H Jr, Rosenwald A, Riedmiller H, Kucherlapati R, Cohen PE, Edelmann W, Kneitz B. Distinct effects of the recurrent Mlh1G67R mutation on MMR functions, cancer, and meiosis. Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4247-52 Peltomäki P, Vasen H. Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database. Dis Markers. 2004;20(4-5):269-76 Chan V, Khoo US, Wong MS, Lau K, Suen D, Li G, Kwong A, Chan TK. Localization of hRad9 in breast cancer. BMC Cancer. 2008 Jul 11;8:196 Toueille M, El-Andaloussi N, Frouin I, Freire R, Funk D, Shevelev I, Friedrich-Heineken E, Villani G, Hottiger MO, Hübscher U. The human Rad9/Rad1/Hus1 damage sensor clamp interacts with DNA polymerase beta and increases its DNA substrate utilisation efficiency: implications for DNA repair. Nucleic Acids Res. 2004;32(11):3316-24 He W, Zhao Y, Zhang C, An L, Hu Z, Liu Y, Han L, Bi L, Xie Z, Xue P, Yang F, Hang H. Rad9 plays an important role in DNA mismatch repair through physical interaction with MLH1. Nucleic Acids Res. 2008 Nov;36(20):6406-17 Hu Z, Liu Y, Zhang C, Zhao Y, He W, Han L, Yang L, Hopkins KM, Yang X, Lieberman HB, Hang H. Targeted deletion of Rad9 in mouse skin keratinocytes enhances genotoxininduced tumor development. Cancer Res. 2008 Jul 15;68(14):5552-61 Wang L, Hsu CL, Ni J, Wang PH, Yeh S, Keng P, Chang C. Human checkpoint protein hRad9 functions as a negative coregulator to repress androgen receptor transactivation in prostate cancer cells. Mol Cell Biol. 2004 Mar;24(5):2202-13 Medhurst AL, Warmerdam DO, Akerman I, Verwayen EH, Kanaar R, Smits VA, Lakin ND. ATR and Rad17 collaborate in modulating Rad9 localisation at sites of DNA damage. J Cell Sci. 2008 Dec 1;121(Pt 23):3933-40 Yin Y, Zhu A, Jin YJ, Liu YX, Zhang X, Hopkins KM, Lieberman HB. Human RAD9 checkpoint control/proapoptotic protein can activate transcription of p21. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8864-9 Zhu A, Zhang CX, Lieberman HB. Rad9 has a functional role in human prostate carcinogenesis. Cancer Res. 2008 Mar 1;68(5):1267-74 Cheng CK, Chow LW, Loo WT, Chan TK, Chan V. The cell cycle checkpoint gene Rad9 is a novel oncogene activated by 11q13 amplification and DNA methylation in breast cancer. Cancer Res. 2005 Oct 1;65(19):8646-54 Doré AS, Kilkenny ML, Rzechorzek NJ, Pearl LH. Crystal structure of the rad9-rad1-hus1 DNA damage checkpoint complex--implications for clamp loading and regulation. Mol Cell. 2009 Jun 26;34(6):735-45 Maniwa Y, Yoshimura M, Bermudez VP, Yuki T, Okada K, Kanomata N, Ohbayashi C, Hayashi Y, Hurwitz J, Okita Y. Accumulation of hRad9 protein in the nuclei of nonsmall cell lung carcinoma cells. Cancer. 2005 Jan 1;103(1):126-32 Sohn SY, Cho Y. Crystal structure of the human rad9-hus1rad1 clamp. J Mol Biol. 2009 Jul 17;390(3):490-502 Ishikawa K, Ishii H, Saito T, Ichimura K. Multiple functions of rad9 for preserving genomic integrity. Curr Genomics. 2006;7(8):477-80 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) This article should be referenced as such: Chan V. RAD9A (RAD9 homolog A (S. pombe)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1145-1148. 1148 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review SCAF1 (SR-related CTD-associated factor 1) Christos Kontos, Andreas Scorilas Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, 157 01, Panepistimiopolis, Athens, Greece (CK, AS) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/SCAF1ID46074ch19q13.html DOI: 10.4267/2042/44918 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology The human SCAF1 gene was shown to be expressed widely in many normal tissues, but its mRNA levels vary a lot. The highest levels of SCAF1 transcripts were detected in the fetal brain and fetal liver and the lowest in salivary gland, skin, heart, uterus and ovary. In the mammary and prostate gland, SCAF1 mRNA transcripts are constitutively present at relatively high levels. The mRNA levels of SCAF1 appear to increase in cancer cell lines treated with various steroid hormones, including estrogens, androgens and glucocorticoids, and to a lesser extent with progestins (Scorilas et al., 2001). Identity Other names: FLJ00034, SCAF, SFRS19, SRA1, SRA1, HGNC (Hugo): SCAF1 Location: 19q13.33 Local order: Telomere to centromere. Note: The first name of this gene, discovered and cloned by Scorilas et al. was SR-A1. After the establishment of the name "SRA1" for steroid receptor RNA activator 1, the official name of SR-A1 gene has changed into SCAF1, to avoid confusion. Pseudogene DNA/RNA Not identified so far. Description Protein Spanning 16.5 kb of genomic DNA, the SCAF1 gene consists of 11 exons and 10 intervening introns (Scorilas et al., 2001). Description The SCAF1 protein is composed of 1312 amino acids, with a calculated molecular mass of 139.1 kDa and a theoretical isoelectric point of 9.31. Transcription The unique transcript of SCAF1 gene is 4313 bp. Schematic representation of the SCAF1 gene. Exons are shown as boxes and introns as connecting lines. Arrows show the positions of the start codon, stop codon, and polyadenylation signal. Roman numerals indicate intron phases. The intron phase refers to the location of the intron within the codon; I denotes that the intron occurs after the first nucleotide of the codon, II that the intron occurs after the second nucleotide, and 0 that the intron occurs between distinct codons. The numbers inside boxes indicate exon lengths and the vertical connecting lines show the intron lengths (in bp). Figure is not drawn to scale. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1149 SCAF1 (SR-related CTD-associated factor 1) Kontos C, Scorilas A Schematic representation of the amino acid sequence of the SCAF1 protein. The Arg/Ser-rich domain is shown in bold and underlined, and the CTD-binding domain is double-underlined. Additionally, the SCAF1 protein contains two areas with negatively charged polyglutamic acid (E) stretches, shown as underlined with dashes, and an Arg/Asp-rich motif, which is normally underlined. Various putative post-translational modification sites have also been identified, including numerous potential sites for either O- or Nglycosylation, and several possible sites of phosphorylation by cAMP-dependent protein kinase (PKA), protein kinase C (PKC), and casein kinase 2. The SCAF1 protein contains an Arg/Ser-rich domain (SR) as well as a CTD-binding domain, present only in a subset of Arg/Ser-rich splicing factors. Through interactions with the pre-mRNA and the Cterminal domain (CTD) of the large subunit of RNA polymerase II, Arg/Ser-rich proteins have been shown to regulate alternative splicing. In addition, we identified two areas with negatively charged polyglutamic acid (E) stretches and an Arg/Asp-rich motif in the SCAF1 protein. This motif is also present in a number of other RNA-binding proteins such as the U1-70 K, the RD RNA-binding protein and the 68 kDa human pre-mRNA cleavage factor Im. Examination of the hydrophobicity profile of the SCAF1 protein did not reveal regions with long stretches of hydrophobic residues. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) SCAF1 is predicted to be a nuclear protein with no transmembrane region. Various putative post-translational modification sites have been identified, including numerous potential sites for either O- or N-glycosylation, and several possible sites of phosphorylation by cAMP-dependent protein kinase (PKA), protein kinase C (PKC), and casein kinase 2 (Scorilas et al., 2001). Expression Currently, there are no data concerning the in vivo expression of the human SCAF1 protein. Localisation The SCAF1 protein is predicted to be localized to the nucleus. 1150 SCAF1 (SR-related CTD-associated factor 1) Kontos C, Scorilas A Function Leukemia SCAF1 interacts with the CTD domain of the RNA polymerase II polypeptide A (POLR2A) and may be involved in pre-mRNA splicing. Prognosis Alterations of SCAF1 mRNA expression have been noticed in the human acute promyelocytic leukemia cell line HL-60, after treatment with cisplatin and bleomycin. mRNA levels of SCAF1 are modulated in both cases as a response to apoptosis induction by each drug, with up-regulation in bleomycin-induced apoptosis and down-regulation in cisplatin-induced apoptosis in HL-60 cells. This differential response of SCAF1 mRNA levels to apoptosis induced by each drug may be due to distinct apoptotic pathways and therefore to distinct cellular needs for the splice variants of specific genes. Cytogenetics No cytogenetic abnormalities have been identified so far. Hybrid/Mutated gene Not identified so far. Homology Human SCAF1 shares 85% amino acid identity and 91% similarity with the mouse and rat Scaf1 protein. Moreover, it shows 25% identity and 48% similarity with the human PHRF1 protein ("PHD and RING finger domain-containing protein 1", also known as "CTD-binding SR-like protein rA9"), and to a lesser extent with other Arg/Ser-rich splicing factors. Mutations No germinal or somatic mutations associated with cancer have been identified so far. Implicated in Breast and ovarian cancer References Prognosis Expression analysis of the SCAF1 gene has showed that SCAF1 mRNA expression may be considered as a new unfavorable prognostic marker for breast and ovarian cancer. Expression of the SCAF1 gene in breast cancer tissues is influenced by the tumor size and the existence of lymph node metastases. Furthermore, high SCAF1 expression is a significant independent prognostic marker of disease-free survival (DFS), and low mRNA expression of the gene is associated with long DFS and overall survival (OS). Regarding SCAF1 gene expression in ovarian cancer, it is positively related to the histological grade and stage of the disease, the size of the tumor, and the debulking success. Additionally, high SCAF1 expression is a significant independent prognostic marker of OS, and low mRNA expression of the gene is related to long DFS and OS. Scorilas A, Kyriakopoulou L, Katsaros D, Diamandis EP. Cloning of a gene (SR-A1), encoding for a new member of the human Ser/Arg-rich family of pre-mRNA splicing factors: overexpression in aggressive ovarian cancer. Br J Cancer. 2001 Jul 20;85(2):190-8 Mathioudaki K, Leotsakou T, Papadokostopoulou A, Paraskevas E, Ardavanis A, Talieri M, Scorilas A. SR-A1, a member of the human pre-mRNA splicing factor family, and its expression in colon cancer progression. Biol Chem. 2004 Sep;385(9):785-90 Katsarou ME, Papakyriakou A, Katsaros N, Scorilas A. Expression of the C-terminal domain of novel human SR-A1 protein: interaction with the CTD domain of RNA polymerase II. Biochem Biophys Res Commun. 2005 Aug 19;334(1):61-8 Leoutsakou T, Talieri M, Scorilas A. Expression analysis and prognostic significance of the SRA1 gene, in ovarian cancer. Biochem Biophys Res Commun. 2006 Jun 2;344(2):667-74 Leoutsakou T, Talieri M, Scorilas A. Prognostic significance of the expression of SR-A1, encoding a novel SR-related CTDassociated factor, in breast cancer. Biol Chem. 2006 Dec;387(12):1613-8 Colon cancer Prognosis SCAF1 mRNA expression seems also to be associated with colon cancer progression, since its expression is higher at the initial stages of tumorigenesis and is reduced as cancer progresses. Katsarou ME, Thomadaki H, Katsaros N, Scorilas A. Effect of bleomycin and cisplatin on the expression profile of SRA1, a novel member of pre-mRNA splicing factors, in HL-60 human promyelocytic leukemia cells. Biol Chem. 2007 Aug;388(8):773-8 This article should be referenced as such: Kontos C, Scorilas A. SCAF1 (SR-related CTD-associated factor 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1149-1151. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1151 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)) Ruo-Chia Tseng, Yi-Ching Wang Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC (RCT, YCW) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/SIRT1ID44006ch10q21.html DOI: 10.4267/2042/44919 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity with a predictive molecular weight of 81.7 kDa and an isoelectric point of 4.55 (Alcaín and Villalba, 2009). Other names: EC 3.5.1, hSIR2, hSIRT1, SIR2alpha, SIR2L1 HGNC (Hugo): SIRT1 Location: 10q21.3 Transcription SIRT1 transcription is under the control of at least two negative feedback loops that keep its induction tightly regulated under conditions of oxidative stress. SIRT1 promoter can be activated by E2F1 and HIC1 during cellular stress. E2F1 directly binds to the SIRT1 promoter at a consensus site located at bp position -65 and appears to regulate the basal expression level of SIRT1. Such high levels of SIRT1 lead to a negative feedback loop where E2F1 activity is inhibited by SIRT1mediated deacetylation. DNA/RNA Description The SIRT1 gene spans about 34 kb including nine exons. The SIRT1 promoter contains a CCAAT box and a number of NFkappaB and GATA transcription factor binding sites in addition to a small 350-bp CpG island in the 5' flanking genomic region. The gene encodes a 747 amino acids protein SIRT1 gene expression is modulated at both transcriptional and posttranscriptional levels. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1152 SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)) By contrast, the tumor suppressor HIC1 and SIRT1 form a transcriptional repression complex that directly binds SIRT1 promoter via its N-terminal POZ domain and represses SIRT1 transcription thereby inhibiting SIRT1-mediated p53 deacetylation and inactivation. Two HIC1 binding sites have been assigned to base pair positions -1116 and -1039 within the SIRT1 promoter. In addition, two functional p53 binding sites (-178 bp and -168 bp), which normally repress SIRT1 expression, have been identified. SIRT1 expression is also regulated at the posttranscriptional level by HuR. It has been demonstrated that HuR, a ubiquitously expressed RNA binding protein, associates with the 3' UTR of the SIRT1 mRNA under physiological conditions and helps to stabilize the transcript. This interaction results in increased SIRT1 mRNA stability and thus in elevated protein levels. Conversely, the HuR-SIRT1 mRNA complex is being disrupted upon oxidative stress, which finally leads to decreased mRNA stability and therefore decreased SIRT protein levels. Tseng RC, Wang YC SIRT1 was the active regulator of SIRT1 (AROS). The AROS protein is known to significantly enhance the activity of SIRT1 on acetylated p53 both in vitro and in cell lines thereby promoting the inhibitory effect of SIRT1 on p53-mediated transcriptional activity of proapoptotic genes (e.g. Bax and p21Waf-1) under conditions of DNA-damage. A negative regulator of SIRT1, DBC-1 (deleted in breast cancer-1), has recently been identified. DBC1 binds directly to the catalytic domain of SIRT1, preventing substrate binding to SIRT1 and inhibiting SIRT1 activity. Reduction of DBC1 inhibits p53-mediated apoptosis after induction of double-stranded DNA breaks owing to SIRT1-mediated p53 deacetylation. Both factors represent the first endogenous, direct regulators of SIRT1 function. Localisation SIRT1 is predominately in the nucleus (although SIRT1 does have some important cytoplasmic functions as well). In addition to possessing two NLSs, SIRT1 contains two nuclear export signals. Thus, the exposure of nuclear localization signals versus nuclear export signals may dictate the cytosolic versus nuclear localization of SIRT1. Pseudogene None identified. Protein Function Description SIRT1 has been reported to play a key role in a variety of physiological processes such as metabolism, neurogenesis and cell survival due to its ability to deacetylate both histone and numerous nonhistone substrates. (1) Lysines 9 and 14 in the amino-terminal tail of histone H3 and lysine 16 of histone H4 are deacetylated by yeast Sir2 and mammalian SIRT1 (Sir2alpha). (2) Metabolic homeostasis is controlled by SIRT1mediated deacetylation and thus activation of the peroxisome proliferation activating receptor (PPAR)gamma co-activator-1a (PGC-1a), which stimulates mitochondrial activity and subsequently increases glucose metabolism, which in turn improves insulin sensitivity. Human SIRT1 encodes 747 amino acids protein with a nuclear localization signal (NLS) at the N-terminus (aa 41-46) and a sirtuin homology domain at the center (aa 261-447); this domain is a conserved catalytic domain for deacetylation. Expression Expression appears to be ubiquitous in adult tissues (although at different levels). Two proteins have been identified to regulate the SIRT1 activity both positively and negatively through complex formation in the context of the cellular stress response. The first identified direct regulator of SIRT1 deacetylase activity is modulated through protein-protein interaction and sumoylation at its three protein domains (Liu T et al., 2009). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1153 SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)) SIRT1 represses PPAR-gamma, a key regulator of adipogenesis, by docking with its cofactors NCoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors). The upregulation of SIRT1 triggers lipolysis and loss of fat. (3) The activation of SIRT1 appears to be neuroprotective in animal models for Alzheimer's disease and amyotrophic lateral sclerosis as well as optic neuritis mainly due to decreased deacetylation of the tumor suppressor p53 and PGC-1a. (4) SIRT1 represses p53-dependent apoptosis in response to DNA damage and oxidative stress and promotes cell survival under cellular stress induced by etoposide treatment or irradiation. (5) SIRT1 activates FOXO1 and FOXO4, which promote cell-cycle arrest by inducing p27kip1; SIRT1 also induces cellular resistance to oxidative stress by increasing the levels of manganese superoxide dismutase and GADD45 (growth arrest and DNA damage-inducible protein 45). (6) SIRT1 inhibits the transcriptional activity of NFkappaB by deacetylating NF-kappaB's subunit, RelA/p65, at lysine 310. Thus, although SIRT1 is capable of protecting cells from p53-induced apoptosis, it may augment apoptosis by repressing NF-kappaB. SIRT1 is reported to bind CTIP2 (BCL11B B-cell CLL/lymphoma 11B) and accelerate the transcriptional repression by this molecule. CTIP2 represses the transcription of its target genes and is implicated in hematopoietic cell development. carcinoma patients with low p53 acetylation and SIRT1 expression mostly showed low HIC1 expression, confirming deregulation HIC1-SIRT1-p53 circular loop in clinical model. Expression of DBC1, which blocks the interaction between SIRT1 deacetylase and p53, led to acetylated p53 in lung adenocarcinoma patients. Prognosis Lung cancer patients with altered HIC1-SIRT1-p53 circular regulation showed poor prognosis. Breast cancer Note The breast cancer associated protein, BCA3, when neddylated (modified by NEDD8) interacts with SIRT1 and suppresses NF-kB-dependent transcription, also sensitizes human breast cancer cells (such as MCF7) to TNF-a-induced apoptosis. In addition, it has been shown recently that SIRT7 levels of expression increase significantly in breast cancer, and that SIRT7 and SIRT3 both are highly transcribed in lymph-node positive breast biopsies, a stage in which the tumour size is at least 2 mm and the cancer has already spread to the lymph nodes. Brain tumor Note SIRT2 resides in a genomic region frequently deleted in human gliomas and ectopic expression of SIRT2 in glioma-derived cell lines markedly reduces their capacity to form colonies in vitro. Exogenously expressed SIRT2 blocks chromosomal condensation and hyperploidy in glioma cell lines, accompanied by the presence of cyclin B/cdc2 activity in response to mitotic stress. Thus, SIRT2 may be a novel metaphase check-point protein that promotes genomic integrity and inhibits the uncontrolled proliferation of transformed cells. Homology SIRT1 is the mammalian homologue closest to yeast NAD+-dependent deacetylase Sir2 (silent information regulation 2). It was originally identified as a lifespan extending gene when over-expressed in budding yeast, Caenorhabditis elegans, and Drosophila melanogaster. The SIR2 gene is broadly conserved in organisms ranging from bacteria to humans. The accession numbers for the amino acid sequences used are as follows: yeast Sir2 (CAA25667), mouse Sir2alpha (AAF24983), human Sirt1 (AAD40849). All of the sirtuin proteins contain the ~275 residue sirtuin homology domain. In many instances a highly conserved protein domain represents a conserved functional binding site for a metabolite or biomolecule and such conserved binding site domains are often found within enzymatic catalytic domains. Kidney diseases Note SIRT1 attenuates TGF-beta (transforming growth factor-beta) apoptotic signaling that is mediated by the effector molecule Smad7. SIRT1-dependent deacetylation of Smad7 at Lys60 and Lys70 enhances its ubiquitin-dependent proteasomal degradation via Smurf1 (Smad ubiquitination regulatory factor 1), thus protecting glomerular mesangial cells from TGF-betadependent apoptosis. Cardiac hypertrophy Implicated in Note Decreasing hypertrophy or apoptosis in cardiac myocytes can ameliorate the disease, and there is reason to suspect that SIRT1 activation may be useful in this regard. SIRT1 protects primary cultured myocytes from programmed cell death induced by serum starvation or by the activation of PARP-1 [poly(ADP-ribose) polymerase-1] in a p53-dependent manner. SIRT1 also deacetylates Lys115 and Lys121 Lung cancer Note Distinct status of p53 acetylation/deacetylation and HIC1 alteration mechanism result from different SIRT1-DBC1 (deleted in breast cancer 1) control and epigenetic alteration in lung squamous cell carcinoma and lung adenocarcinoma. The lung squamous cell Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Tseng RC, Wang YC 1154 SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)) Tseng RC, Wang YC of the histone variant H2A.Z, a factor known to promote cardiac hypertrophy. In doing so, SIRT1 promotes the ubiquitination and proteosome-dependent degradation of H2A.Z, which may help to protect against heart failure. transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004 Jun 16;23(12):2369-80 References Hisahara S, Chiba S, Matsumoto H, Horio Y. Transcriptional regulation of neuronal genes and its effect on neural functions: NAD-dependent histone deacetylase SIRT1 (Sir2alpha). J Pharmacol Sci. 2005 Jul;98(3):200-4 Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB. Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53dependent DNA-damage responses. Cell. 2005 Nov 4;123(3):437-48 Frye RA. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem Biophys Res Commun. 1999 Jun 24;260(1):273-9 Kobayashi Y, Furukawa-Hibi Y, Chen C, Horio Y, Isobe K, Ikeda K, Motoyama N. SIRT1 is critical regulator of FOXOmediated transcription in response to oxidative stress. Int J Mol Med. 2005 Aug;16(2):237-43 Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 1999 Oct 1;13(19):2570-80 Pillai JB, Isbatan A, Imai S, Gupta MP. Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2alpha deacetylase activity. J Biol Chem. 2005 Dec 30;280(52):43121-30 Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NADdependent histone deacetylase. 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Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1152-1156. Zhao W, Kruse JP, Tang Y, Jung SY, Qin J, Gu W. Negative regulation of the deacetylase SIRT1 by DBC1. Nature. 2008 Jan 31;451(7178):587-90 Zschoernig B, Mahlknecht U. SIRTUIN 1: regulating the regulator. Biochem Biophys Res Commun. 2008 Nov 14;376(2):251-5 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Tseng RC, Wang YC 1156 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review SLC16A3 (solute carrier family 16, member 3 (monocarboxylic acid transporter 4)) Céline Pinheiro, Fátima Baltazar Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal (CP, FB) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/SLC16A3ID44573ch17q25.html DOI: 10.4267/2042/44920 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology cells, chondrocytes, testis, lung, placenta, heart and some mammalian cell lines (Halestrap and Meredith, 2004; Meredith and Christian, 2008). Identity Other names: MCT3, MGC138474 HGNC (Hugo): SLC16A3 Location: 17q25.3 MCT4, MGC138472, Localisation Plasma membrane. Function DNA/RNA Note SLC16A3 was first cloned from human circulating blood by Price et al. (1998). Proton-linked monocarboxylate transporter. Catalyzes plasma membrane transport of monocarboxylates such as lactate, pyruvate, branched-chain oxo acids derived from leucine, valine and isoleucine, and the ketone bodies acetoacetate, beta-hydroxybutyrate and acetate. Description Homology 11077 bp lenght, 5 exons. Belongs to the major facilitator superfamily (MFS). Monocarboxylate porter (TC 2.A.1.13) family. The SLC16A3 gene is conserved in chimpanzee, dog, cow, mouse, rat, chicken, zebrafish, and M. grisea. Transcription 3 transcripts have been described for this gene (all with protein product): SLC16A3-201, (5 exons; 2033 bps transcript length; 465 residues translation length); SLC16A3-202 (4 exons; 4222 bps transcript length; 465 residues translation length); SLC16A3-203 (5 exons; 2054 bps transcript length; 465 residues translation length). Implicated in Colorectal carcinoma Note SLC16A3/MCT4 protein is overexpressed in colorectal cancer (Pinheiro et al., 2008a). Protein Cervical cancer Description Note SLC16A3/MCT4 protein is overexpressed in cervical cancer (Pinheiro et al., 2008b). SLC16A3/MCT4 protein overexpression in cervical cancer correlated with positivity for high-risk HPV (Pinheiro et al., 2008b). 465 residues; 49469 Da; 12 transmembrane domains; intracellular N- and C-terminals. Expression SLC16A3/MCT4 is expressed in tissues such as white skeletal muscle fibres, astrocytes, white blood Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1157 SLC16A3 (solute carrier family 16, member 3 (monocarboxylic acid transporter 4)) Pinheiro C, Baltazar F Protein diagram drawn following UniProtKB/Swiss-Prot database prediction, using TMRPres2D software. a patient with a mitochondrial myopathy (Baker et al., 2001). Bladder cancer Note SLC16A3 gene expression was upregulated in some bladder tumours and induced by hypoxia in bladder cancer cell lines, but not in cultures of normal urothelium (Ord et al., 2005). Chronic obstructive pulmonary disease Note SLC16A3/MCT4 downregulation was described in the vastus lateralis muscle of patients with chronic obstructive pulmonary disease as compared with healthy controls (Green et al., 2008). Breast cancer Note Induction was also seen in two breast cancer cell lines. Expression of SLC16A3 gene is higher in breast cancer distant metastasis as compared to primary tumours or regional metastasis. SLC16A3 gene was then included in the 'VEGF profile' of breast cancer, associated with promotion of vessel formation, survival under anaerobic conditions and loss of dependence upon fibroblasts (Hu et al., 2009). References Price NT, Jackson VN, Halestrap AP. Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past. Biochem J. 1998 Jan 15;329 ( Pt 2):321-8 Baker SK, Tarnopolsky MA, Bonen A. Expression of MCT1 and MCT4 in a patient with mitochondrial myopathy. Muscle Nerve. 2001 Mar;24(3):394-8 Ovarian cancer Halestrap AP, Meredith D. The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch. 2004 Feb;447(5):61928 Note SLC16A3 gene expression was described to be downregulated in malignant ovarian tumours as compared to normal ovarian surface epithelial cells. Additionally, the non-tumorigenic cell line TOV-81D presented higher expression that tumorigenic cell lines (Wojnarowicz et al., 2008). SLC16A3 gene, among other transporter genes, was differentially expressed in a chemotherapy resistant ovarian cancer cell line and tumour tissue as compared to a chemosensitive cell line and tumour tissue. It was suggested that these transporters might be involved in drug influx/efflux, modulating chemotherapy response (Cheng et al., 2010). Ord JJ, Streeter EH, Roberts IS, Cranston D, Harris AL. Comparison of hypoxia transcriptome in vitro with in vivo gene expression in human bladder cancer. Br J Cancer. 2005 Aug 8;93(3):346-54 Green HJ, Burnett ME, D'Arsigny CL, O'Donnell DE, Ouyang J, Webb KA. Altered metabolic and transporter characteristics of vastus lateralis in chronic obstructive pulmonary disease. J Appl Physiol. 2008 Sep;105(3):879-86 Meredith D, Christian HC. The SLC16 monocaboxylate transporter family. Xenobiotica. 2008 Jul;38(7-8):1072-106 Pinheiro C, Longatto-Filho A, Ferreira L, Pereira SM, Etlinger D, Moreira MA, Jubé LF, Queiroz GS, Schmitt F, Baltazar F. Increasing expression of monocarboxylate transporters 1 and 4 along progression to invasive cervical carcinoma. Int J Gynecol Pathol. 2008 Oct;27(4):568-74 Mitochondrial myopathy Note SLC16A3/MCT4 overexpression was described in Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1158 SLC16A3 (solute carrier family 16, member 3 (monocarboxylic acid transporter 4)) Pinheiro C, Longatto-Filho A, Scapulatempo C, Ferreira L, Martins S, Pellerin L, Rodrigues M, Alves VA, Schmitt F, Baltazar F. Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas. Virchows Arch. 2008 Feb;452(2):139-46 Perou CM. A compact VEGF signature associated with distant metastases and poor outcomes. BMC Med. 2009 Mar 16;7:9 Cheng L, Lu W, Kulkarni B, Pejovic T, Yan X, Chiang JH, Hood L, Odunsi K, Lin B. Analysis of chemotherapy response programs in ovarian cancers by the next-generation sequencing technologies. Gynecol Oncol. 2010 May;117(2):159-69 Wojnarowicz PM, Breznan A, Arcand SL, Filali-Mouhim A, Provencher DM, Mes-Masson AM, Tonin PN. Construction of a chromosome 17 transcriptome in serous ovarian cancer identifies differentially expressed genes. Int J Gynecol Cancer. 2008 Sep-Oct;18(5):963-75 This article should be referenced as such: Pinheiro C, Baltazar F. SLC16A3 (solute carrier family 16, member 3 (monocarboxylic acid transporter 4)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1157-1159. Hu Z, Fan C, Livasy C, He X, Oh DS, Ewend MG, Carey LA, Subramanian S, West R, Ikpatt F, Olopade OI, van de Rijn M, Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Pinheiro C, Baltazar F 1159 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review SPAM1 (sperm adhesion molecule 1 (PH-20 hyaluronidase, zona pellucida binding)) Asli Sade, Sreeparna Banerjee Department of Biology, Middle East Technical University, Ankara 06531, Turkey (AS, SB) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/SPAM1ID42361ch7q31.html DOI: 10.4267/2042/44921 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology are clustered on chromosome 3p21.3 and the other three (HYAL4, SPAM1 and HYALP1) are clustered on chromosome 7q31.3. Of the three genes on chromosome 7q31.3, HYALP1 is an expressed pseudogene. The extensive homology between the six hyaluronidase genes suggests an ancient gene duplication event before the emergence of modern mammals. Identity Other names: EC 3.2.1.35, HYA1, HYAL1, HYAL3, HYAL5, Hyal-PH20, MGC26532, PH-20, PH20, SPAG15 HGNC (Hugo): SPAM1 Location: 7q31.32 Local order: According to NCBI Map Viewer, genes flanking SPAM1 in centromere to telomere direction on 7q31.3 are: HYALP1 7q31.3 hyaluronoglucosaminidase pseudogene 1 - HYAL4 7q31.3 hyaluronoglucosaminidase 4 - SPAM1 7q31.3 sperm adhesion molecule 1 - TMEM229A 7q31.32 transmembrane protein 229A - hCG_1651160 7q31.33 SSU72 RNA polymerase II CTD phosphatase homolog pseudogene Note: SPAM1 is a glycosyl-phosphatidyl inositol (GPI)-anchored enzyme found in all mammalian spermatozoa. The protein has a hyaluronidase activity that enables sperm to penetrate the cumulus, a role in zona pellucida binding and also participates in Ca2+ signaling associated acrosomal exocytosis. Description According to Entrez Gene, SPAM1 gene maps to locus NC_000007 and spans a region of 46136 bp. According to Spidey (mRNA to genomic sequence alignment tool), SPAM1 has 7 exons, the sizes being 78, 112, 1160, 90, 441, 99 and 404. Transcription The SPAM1 mRNA has two isoforms; transcript variant 1 (NM_003117) a 2395 bp mRNA and transcript variant 2 (NM_153189) a 2009 bp mRNA. The variant 2 uses an alternate in-frame splice site in the 3' coding region, compared to variant 1, resulting in a shorter C-terminus. The promoter region of SPAM1 has been shown to contain a CRE (cAMP-responsive element) sequence which is a binding site for CREM (cAMP-responsive element modulator) and thus Spam1 is under a cAMPdependent transcriptional regulation. No TATA or CCAAT boxes were found in the promoter region of SPAM1. DNA/RNA Note The human genome contains six hyaluronidase like genes. Three of them (HYAL1, HYAL2 and HYAL3) The diagram of SPAM1 transcript variant 1. The red boxes represent the exons (in scale) and exon numbers are given below the boxes. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1160 SPAM1 (sperm adhesion molecule 1 (PH-20 hyaluronidase, zona pellucida binding)) The testis-specific promoters of the human and mouse SPAM1 genes are derived from a sequence that was originally part of an ERV pol gene. Sade A, Banerjee S The human SPAM1 pseudogene HYALP1 is located on chromosome 7q31.3. responsible for local degradation of the cumulus ECM during sperm penetration. Plasma membrane SPAM1 mediates HA-induced sperm signaling via the HA binding domain. SPAM1 is also secreted by the epithelial cells of the epididymis and has a role in sperm maturation. In addition SPAM1 is implicated in fluid reabsorption and urine concentration in kidney. Protein Homology Pseudogene - Pan troglodytes sperm adhesion molecule 1 (SPAM1) - Canis lupus familiaris sperm adhesion molecule 1 (SPAM1) - Bos taurus sperm adhesion molecule 1 (SPAM1) - Mus musculus hyaluronoglucosaminidase 5 (Hyal5) - Mus musculus sperm adhesion molecule 1 (SPAM1) - Rattus norvegicus sperm adhesion molecule 1 (HYALP_RAT) - Gallus gallus sperm adhesion molecule 1 (SPAM1) - Danio rerio sperm adhesion molecule 1 (Spam1) Note Two sperm adhesion isoforms exist; one is 511 aa long isoform 1 and the other 509 aa long isoform 2. When the two isoforms are aligned the sequences are 100% identical and no functional difference has been reported. Description SPAM1 is a 68 kDa protein that belongs to glycosyl hydrolase 56 family. This family of enzymes has hyaluronidase activity which hydrolyses the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. Sperm hyaluronidase is active at neutral and acidic pHs which results from different active sites in the hyaluronidase domain at the N-terminus of the protein. The hyaluronidase domain also contains a hyaluronic acid (HA) binding site that plays a role in the signaling pathway leading to acrosomal exocytosis. The protein also contains a zona binding domain at the C-terminal end. Mutations Note According to dbSNP, one validated missense SNP for SPAM1 is found in the 47th aa position causing a V to A (rs34633019) substitution. Other SNPs causing synonymous changes are: rs34404662 A/G substitution at the 3rd amino acid residue (Val), rs2285996 A/G substitution at the 184th amino acid residue (Lys) and rs34978112 C/T substitution at the 330th amino acid residue (Ala). No clinical associations with these SNPs have been reported. Expression Germinal According to GNF Expression Atlas 2 Data from U133A and GNF1H Chips, SPAM1 expression is widely limited to testis and epididymis but it was also found to be expressed in murine kidney and female reproductive tract. Both rare and abundant SPAM1 transcripts have been found in neoplastic breast tissue and in a number of other cancers including pharyngeal astatic melanomas and gliomas. In normal somatic cells rare transcripts have been found in breast tissue and in fetal, placental, and prostate cDNA libraries. In mice bearing Robertsonian translocation Rb(6.15) and (6.16), reduced Spam1 hyaluronidase activity was found to cause sperm dysfunction. It was proposed that entrapment of spontaneous Spam1 mutations, owing to recombination suppression near the Rb junctions was the major effect. According to in vitro mutagenesis experiments the following mutations were detected to have functional consequences: - D146N: 80% loss of activity - E148Q: loss of activity - R211G: 90% loss of activity - E284Q: loss of activity - R287T: loss of activity Localisation SPAM1 is located on the sperm surface and in the lysosome-derived acrosome, where it is bound to the inner acrosomal membrane. The acrosomal membrane SPAM1 differs biochemically from the one on the sperm surface. Implicated in Function Breast cancer SPAM1 is a multifunctional protein; a hyaluronidase that acts in penetrating the cumulus, a receptor for hyaluronic acid induced cell signaling which leads to acrosomal exocytosis and a receptor for the zona pellucida surrounding the oocyte. The zona pellucida recognition function is ascribed to the inner acrosomal membrane SPAM1. The neutral enzyme activity of plasma membrane SPAM1, which is GPI anchored, is Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Oncogenesis Increased levels of SPAM1 are noted in invasive and metastatic breast cancer compared to ductal carcinoma in situ (DCIS). Tumors from African American women with invasive and metastatic breast cancer showed higher levels of SPAM1 than Caucasians. Varying levels of SPAM1 in mammary 1161 SPAM1 (sperm adhesion molecule 1 (PH-20 hyaluronidase, zona pellucida binding)) Sade A, Banerjee S tissue may contribute to early invasion and metastasis of breast cancer. dysfunction in Rb(6.16)24Lub and Rb(6.15)1Ald heterozygotes. Mamm Genome. 1997 Feb;8(2):94-7 Laryngeal cancer Sun L, Feusi E, Sibalic A, Beck-Schimmer B, Wüthrich RP. Expression profile of hyaluronidase mRNA transcripts in the kidney and in renal cells. Kidney Blood Press Res. 1998;21(6):413-8 Oncogenesis SPAM1 expression was found to be significantly elevated in primary laryngeal cancer tissue and even higher in metastatic lesions compared with normal laryngeal tissue. SPAM1 may therefore be a useful tumor marker and prognostic tool for laryngeal cancer. In squamous cell laryngeal carcinoma aberrant expression of SPAM1 at late stages of cancer was detected. Zheng Y, Martin-Deleon PA. Characterization of the genomic structure of the murine Spam1 gene and its promoter: evidence for transcriptional regulation by a cAMP-responsive element. Mol Reprod Dev. 1999 Sep;54(1):8-16 Godin DA, Fitzpatrick PC, Scandurro AB, Belafsky PC, Woodworth BA, Amedee RG, Beech DJ, Beckman BS. PH20: a novel tumor marker for laryngeal cancer. Arch Otolaryngol Head Neck Surg. 2000 Mar;126(3):402-4 Colon Cancer Cherr GN, Yudin AI, Overstreet JW. The dual functions of GPIanchored PH-20: hyaluronidase and intracellular signaling. Matrix Biol. 2001 Dec;20(8):515-25 Oncogenesis SPAM1 mRNA was present in mRNA from four biopsies obtained from patients with colorectal cancers. Normal colonic mucosal tissues obtained from the same patients did not express SPAM1 mRNA. In metastatic colon carcinoma cell lines but not in nonmetastatic cell lines, SPAM1 expression was detected. Strong angiogenesis developed in four of five animals injected with SPAM1+ colon carcinoma VAC05 cells. However, only one of five animals injected with SPAM1- VAC06 cells developed significant angiogenesis. Csoka AB, Frost GI, Stern R. The six hyaluronidase-like genes in the human and mouse genomes. Matrix Biol. 2001 Dec;20(8):499-508 Vines CA, Li MW, Deng X, Yudin AI, Cherr GN, Overstreet JW. Identification of a hyaluronic acid (HA) binding domain in the PH-20 protein that may function in cell signaling. Mol Reprod Dev. 2001 Dec;60(4):542-52 Zheng Y, Deng X, Zhao Y, Zhang H, Martin-DeLeon PA. Spam1 (PH-20) mutations and sperm dysfunction in mice with the Rb(6.16) or Rb(6.15) translocation. Mamm Genome. 2001 Nov;12(11):822-9 Beech DJ, Madan AK, Deng N. Expression of PH-20 in normal and neoplastic breast tissue. J Surg Res. 2002 Apr;103(2):2037 Melanoma Oncogenesis SPAM1 expression is seen in metastatic melanoma but not in non-metastatic melanoma cell lines (SMMU-2 and SMMU-1 respectively). SPAM1+ human melanoma cell line SMMU-2 but not SPAM1- SMMU1 cells induced angiogenesis in mice cornea although the exact mechanisms of how SPAM1 induces angiogenesis is not known. Evans EA, Zhang H, Martin-DeLeon PA. SPAM1 (PH-20) protein and mRNA expression in the epididymides of humans and macaques: utilizing laser microdissection/RT-PCR. Reprod Biol Endocrinol. 2003 Aug 6;1:54 Zhang H, Martin-DeLeon PA. Mouse Spam1 (PH-20) is a multifunctional protein: evidence for its expression in the female reproductive tract. Biol Reprod. 2003 Aug;69(2):446-54 Dunn CA, Mager DL. Transcription of the human and rodent SPAM1 / PH-20 genes initiates within an ancient endogenous retrovirus. BMC Genomics. 2005 Apr 1;6(1):47 References Christopoulos TA, Papageorgakopoulou N, Theocharis DA, Mastronikolis NS, Papadas TA, Vynios DH. Hyaluronidase and CD44 hyaluronan receptor expression in squamous cell laryngeal carcinoma. Biochim Biophys Acta. 2006 Jul;1760(7):1039-45 Jones MH, Davey PM, Aplin H, Affara NA. Expression analysis, genomic structure, and mapping to 7q31 of the human sperm adhesion molecule gene SPAM1. Genomics. 1995 Oct 10;29(3):796-800 Liu D, Pearlman E, Diaconu E, Guo K, Mori H, Haqqi T, Markowitz S, Willson J, Sy MS. Expression of hyaluronidase by tumor cells induces angiogenesis in vivo. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7832-7 Grigorieva A, Griffiths GS, Zhang H, Laverty G, Shao M, Taylor L, Martin-DeLeon PA. Expression of SPAM1 (PH-20) in the murine kidney is not accompanied by hyaluronidase activity: evidence for potential roles in fluid and water reabsorption. Kidney Blood Press Res. 2007;30(3):145-55 Arming S, Strobl B, Wechselberger C, Kreil G. In vitro mutagenesis of PH-20 hyaluronidase from human sperm. Eur J Biochem. 1997 Aug 1;247(3):810-4 This article should be referenced as such: Deng X, Moran J, Copeland NG, Gilbert DJ, Jenkins NA, Primakoff P, Martin-DeLeon PA. The mouse Spam1 maps to proximal chromosome 6 and is a candidate for the sperm Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Sade A, Banerjee S. SPAM1 (sperm adhesion molecule 1 (PH20 hyaluronidase, zona pellucida binding)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1160-1162. 1162 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review TMPRSS2 (transmembrane protease, serine 2) Youngwoo Park Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea (YP) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/TMPRSS2ID42592ch21q22.html DOI: 10.4267/2042/44922 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Localisation Identity Subcellular location: Cell membrane; Single-pass type II membrane protein. Activated by cleavage and secreted. Other names: FLJ41954, PP9284, PRSS10 HGNC (Hugo): TMPRSS2 Location: 21q22.3 Function DNA/RNA Two alternative splicing variants have been described, producing transcripts of 3.25 kb and 3.21 kb, respectively. This gene was demonstrated to be up-regulated by androgenic hormones in prostate cancer cells and down-regulated in androgen-independent prostate cancer tissue. To containing intra- and extracellular domains, TMPRSS2 could work as a receptor for specific ligand(s) mediating signals between the environment and the cell. TMPRSS2 has been proposed to regulate epithelial sodium currents in the lung through proteolytic cleavage of the epithelial sodium channel and inflammatory responses in the prostate via the proteolytic activation of PAR-2. Protein Homology Description TMPRSS2 gene approximately extends 43.59 kb-long on chromosome 21 in the region q22.3, containing 14 exons. Transcription TTPs (type II transmembrane serine proteases) contain an integral transmembrane domain and remain cellsurface-associated, even after proteolytic activation of the protease zymogen. Human TTSPs, which consists of 17 members, were grouped into four subfamilies based on similarity in domain structure and phylogenetic analysis of the serine protease domains, namely the matriptase, corin, hepsin/TMPRSS and HAT/DESC subfamilies. Description TMPRSS2 is a 492 amino acid type II transmembrane serine proteases (TTSPs) which are expressed at the cell surface and are thus ideally located to regulate cellcell and cell-matrix interactions. Expression TMPRSS2 is expressed in normal and diseased human tissues. Especially, TMPRSS2 is highly expressed in small intestine, but also in lower levels in several other tissues. Also expressed in prostate, colon, stomach and salivary gland. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1163 TMPRSS2 (transmembrane protease, serine 2) Park Y TMPRSS2 is a 492 amino acid single-pass type II membrane protein. It contains a Serine protease domain (aa 255-492) of the S1 family, followed by a Scavenger receptor cysteine-rich domain (SRDR, aa 149-242) of group A; an LDL receptor class A (LDLRA, aa 113-148) domain forms a binding site for calcium; a predicted transmembrane domain (aa 84-106). Letters H, D and S in the serine protease domain indicate the position of the three catalytic residues histidine, aspartate and serine, respectively. Multidomain structure of human TTSPs. Human TTSPs were grouped into four subfamilies based on similarity in domain structure and phylogenetic analysis of the serine protease domains, namely the matriptase, corin, hepsin/TMPRSS and HAT/DESC subfamilies. Consensus domains are shown below. Each diagram was drawn using the web-based SMART software (http://smart.emblheidelberg.de) with TTSP amino acid sequences obtained from GenBank. Abbreviations: CUB, Cls/Clr, urchin embryonic growth factor and bone morphogenic protein-1 domain; DESC1, differentially expressed squamous cell carcinoma gene 1; FRZ, frizzled domain; HAT, human airway trypsin-like protease; LDLA, low-density lipoprotein receptor domain class A; MAM, a meprin, A5 antigen and receptor protein phosphatase m domain; MSPL, mosaic serine protease long-form; Polyserase-1, polyserine protease-1; SEA, a single sea urchin sperm protein, enteropeptidase, agrin domain; SR, scavenger receptor cysteine-rich domain; TM, transmembrane domain. Letters H, D and S in the serine protease domain (active) indicate the position of the three catalytic residues histidine, aspartate and serine, respectively. Letter A in the serine protease domain (inactive) indicates a serine to alanine exchange. however, its gene turned out to be expressed mainly in the prostate in an androgen dependent manner. In the prostate adenocarcinoma, TMPRSS2-EGR fusion mRNAs is highly expressed. Because of its location on the surface of prostatic cells, TMPRSS2 is a potential new diagnostic marker for prostate cancer. Implicated in Prostate cancer Prognosis TMPRSS2 was originally reported to smallintestine-associated serine protease. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) be a Later, 1164 TMPRSS2 (transmembrane protease, serine 2) Park Y Breakpoints References Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE. Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3. Genomics. 1997 Sep 15;44(3):309-20 Bugge TH, Antalis TM, Wu Q. Type II transmembrane serine proteases. J Biol Chem. 2009 Aug 28;284(35):23177-81 Choi SY, Bertram S, Glowacka I, Park YW, Pöhlmann S. Type II transmembrane serine proteases in cancer and viral infections. Trends Mol Med. 2009 Jul;15(7):303-12 Vaarala MH, Porvari K, Kyllönen A, Lukkarinen O, Vihko P. The TMPRSS2 gene encoding transmembrane serine protease is overexpressed in a majority of prostate cancer patients: detection of mutated TMPRSS2 form in a case of aggressive disease. Int J Cancer. 2001 Dec 1;94(5):705-10 Barwick BG, Abramovitz M, Kodani M, Moreno CS, Nam R, Tang W, Bouzyk M, Seth A, Leyland-Jones B. Prostate cancer genes associated with TMPRSS2-ERG gene fusion and prognostic of biochemical recurrence in multiple cohorts. Br J Cancer. 2010 Feb 2;102(3):570-6 Vaarala MH, Porvari KS, Kellokumpu S, Kyllönen AP, Vihko PT. Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues. J Pathol. 2001 Jan;193(1):13440 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) This article should be referenced as such: Park Y. TMPRSS2 (transmembrane protease, serine 2). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1163-1165. 1165 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review TMSB10 (thymosin beta 10) Xueshan Qiu Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, China (XQ) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/TMSB10ID42595ch2p11.html DOI: 10.4267/2042/44923 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Localisation Identity TMSB10 is expressed in cytoplasm. Other names: MIG12, TB10, THYB10 HGNC (Hugo): TMSB10 Location: 2p11.2 Note: TMSB10 is a member of the beta-thymosin family, which is an actin-sequestering protein involved in cell motility. TMSB10 may be correlated with tumor cells proliferation, apoptosis, metastasis and angiogenesis. Function Overview: TMSB10 is a highly conserved small acid protein. It is present in many tissues and cell types. It can sequester actin monomers and bind to G-actin in a 1:1 complex. Actin monomer sequestering protein: TMSB10 is one of G-actin binding proteins, being expressed in all mammalian species. It can sequester monomeric actin and inhibit actin polymerization. It participates in the regulation of cancer cell motility. Development: The expression of TMSB10 is associated with the development of several tissues. It is involved in the development of the oral cavity and its annexes. TMSB10 plays an important role in early neuroembryogenesis. It is present in the developing nervous, and has a specific physiological function during cerebellum development. TMSB10 is only present at very low levels in a very small subpopulation of glia in the adult cerebellum. In young animals, most of the TMSB10 is localized in granule cells, Golgi neurons and Purkinje cells. In old animals, TMSB10 signal is detected faintly in a few Purkinje cells. Apoptosis: TMSB10 regulates apoptosis. For example, upregulation of TMSB10 in M. bovis-infected macrophages is linked with increased cell death due to apoptosis. DNA/RNA Description The cDNA sequence for human TMSB10 is 482 nucleotides long comprising 3 exons. The open reading frame of the coding region is 135 bp. Protein Description Protein length (NP_066926.1): 44 amino acids. (madkpdmgeiasfdkaklkktetqekntlptketieqekrseis) Molecular weight: 4.9 kDa. TMSB10 is a small G-actin binding protein, and it induces depolymerization of intracellular F-actin pools by sequestering actin monomers. Expression TMSB10 is found in human, rat, mouse, cat, and rabbit. TMSB10 is one of the most abundant beta-thymosins. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1166 TMSB10 (thymosin beta 10) Qiu X TMSB10 can disrupt F-actin stress fibers, markedly decrease ovarian cancer cells growth, and a high rate of apoptosis. TMSB10 plays a significant role in cell apoptosis possibly by acting as an actin-mediated tumor suppressor, perhaps functions as a neoapoptotic influence during embryogenesis, and may mediate some of the pro-apoptotic anticancer actions of retinoids. Angiogenesis: TMSB10 may be an effective inhibitor of angiogenesis by inhibiting endothelial migration, tube formation, VEGF, VEGFR-1 and integrin alphaV expression in HCAECs. TMSB10 is not only a cytoskeletal regulator, it also acts as a potent inhibitor of angiogenesis and tumor growth by interaction with Ras. Cancers: Elevated expression of TMSB10 is associated with invasion and metastasis of several kinds of tumors. It may be considered a potential tool for the diagnosis of several human neoplasias. TMSB10 is detected mainly in the malignant tissue, particularly in the cancerous cells, whereas the normal cell population around the lesions showed very weak staining. Also, the intensity of staining in the cancerous cells is proportionally increased with the increasing grade of the lesions. Breast cancer Note TMSB10 plays a key role in sequestration of Gactin as well as in breast cancer cell motility. Ovarian cancer Note TMSB10 inhibits angiogenesis and tumor growth by interfering Ras signal transduction and expression of VEGF. Thyroid neoplasias Note TMSB10 overexpression is a general event of thyroid cell neoplastic transformation. An increased expression of TMSB10 mRNA in thyroid carcinomas is found. The evaluation of TMSB10 gene expression may be considered a promising means of human thyroid hyperproliferative diagnosis. By decreasing TMSB10 expression, the thyroid cancer cells growth in soft agar is inhibited. Renal cell carcinoma Note The TMSB10 gene is deregulated in renal cell carcinoma and it may be a new molecular marker for renal-cell carcinoma. Homology Homolog to thymosin beta 4 and thymosin beta 15. Cutaneous melanoma Implicated in Note TMSB10 can be considered as a new progression marker for human cutaneous melanoma. Pancreatic cancer Note TSMB10 is expressed in human pancreatic carcinoma, but not in non-neoplastic pancreatic tissue, suggesting a role for TMSB10 in the carcinogenesis of pancreatic carcinoma. It is a promising marker and a novel therapeutic target for pancreatic cancer. Exogenous TMSB10 causes the phosphorylation of JNK and increases the secretion of cytokines interleukin (IL)-7 and IL-8 in BxPC-3 pancreatic cancer cells. References Erickson-Viitanen S, Ruggieri S, Natalini P, Horecker BL. Thymosin beta 10, a new analog of thymosin beta 4 in mammalian tissues. Arch Biochem Biophys. 1983 Sep;225(2):407-13 Abiko T, Sekino H. Synthesis of deacetyl-thymosin beta 10 and examination of its immunological effect on T-cell subpopulations of a uremic patient with tuberculosis. Chem Pharm Bull (Tokyo). 1986 Nov;34(11):4708-17 Non-small cell lung cancer Goodall GJ, Horecker BL. Molecular cloning of the cDNA for rat spleen thymosin beta 10 and the deduced amino acid sequence. Arch Biochem Biophys. 1987 Jul;256(1):402-5 Note TMSB10 might induce microvascular and lymphatic vessel formation by up-regulating vascular endothelial growth factor and vascular endothelial growth factor-C in lung cancer tissues, thus promoting the distant and lymph node metastases and being implicated in the progression of non-small cell lung cancer. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) McCreary V, Kartha S, Bell GI, Toback FG. Sequence of a human kidney cDNA clone encoding thymosin beta 10. Biochem Biophys Res Commun. 1988 Apr 29;152(2):862-6 Hall AK, Hempstead J, Morgan JI. Thymosin beta 10 levels in developing human brain and its regulation by retinoic acid in the HTB-10 neuroblastoma. Brain Res Mol Brain Res. 1990 Jul;8(2):129-35 1167 TMSB10 (thymosin beta 10) Qiu X Lin SC, Morrison-Bogorad M. Developmental expression of mRNAs encoding thymosins beta 4 and beta 10 in rat brain and other tissues. J Mol Neurosci. 1990;2(1):35-44 Huff T, Müller CS, Hannappel E. C-terminal truncation of thymosin beta10 by an intracellular protease and its influence on the interaction with G-actin studied by ultrafiltration. FEBS Lett. 1997 Sep 1;414(1):39-44 Hall AK. Developmental regulation of thymosin beta 10 mRNA in the human brain. Brain Res Mol Brain Res. 1991 Jan;9(12):175-7 Hall AK. Differential expression of thymosin genes in human tumors and in the developing human kidney. 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Thymosin beta-10 gene overexpression is a general event in human carcinogenesis. Am J Pathol. 1999 Sep;155(3):799-804 Lin SC, Morrison-Bogorad M. Cloning and characterization of a testis-specific thymosin beta 10 cDNA. Expression in postmeiotic male germ cells. J Biol Chem. 1991 Dec 5;266(34):23347-53 Vassiliadou I, Leondiadis L, Ferderigos N, Ithakissios DS, Evangelatos GP, Livaniou E. Investigation of the epitopic structure of thymosin beta10 by epitope mapping experiments. Peptides. 1999;20(3):411-4 Lugo DI, Chen SC, Hall AK, Ziai R, Hempstead JL, Morgan JI. Developmental regulation of beta-thymosins in the rat central nervous system. J Neurochem. 1991 Feb;56(2):457-61 Viglietto G, Califano D, Bruni P, Baldassarre G, Vento MT, Belletti B, Fedele M, Santelli G, Boccia A, Manzo G, Santoro M, Fusco A. Regulation of thymosin beta10 expression by TSH and other mitogenic signals in the thyroid gland and in cultured thyrocytes. Eur J Endocrinol. 1999 Jun;140(6):597-607 Condon MR, Hall AK. Expression of thymosin beta-4 and related genes in developing human brain. J Mol Neurosci. 1992;3(3):165-70 Anadón R, Rodríguez Moldes I, Carpintero P, Evangelatos G, Livianou E, Leondiadis L, Quintela I, Cerviño MC, GómezMárquez J. Differential expression of thymosins beta(4) and beta(10) during rat cerebellum postnatal development. Brain Res. 2001 Mar 16;894(2):255-65 Hall AK. Retinoids and a retinoic acid receptor differentially modulate thymosin beta 10 gene expression in transfected neuroblastoma cells. Cell Mol Neurobiol. 1992 Feb;12(1):45-58 Border BG, Lin SC, Griffin WS, Pardue S, Morrison-Bogorad M. Alterations in actin-binding beta-thymosin expression accompany neuronal differentiation and migration in rat cerebellum. J Neurochem. 1993 Dec;61(6):2104-14 Bani-Yaghoub M, Felker JM, Ozog MA, Bechberger JF, Naus CC. Array analysis of the genes regulated during neuronal differentiation of human embryonal cells. Biochem Cell Biol. 2001;79(4):387-98 Nachmias VT. Small actin-binding proteins: the beta-thymosin family. Curr Opin Cell Biol. 1993 Feb;5(1):56-62 Weterman MA, van Muijen GN, Ruiter DJ, Bloemers HP. Thymosin beta-10 expression in melanoma cell lines and melanocytic lesions: a new progression marker for human cutaneous melanoma. Int J Cancer. 1993 Jan 21;53(2):278-84 Koutrafouri V, Leondiadis L, Avgoustakis K, Livaniou E, Czarnecki J, Ithakissios DS, Evangelatos GP. Effect of thymosin peptides on the chick chorioallantoic membrane angiogenesis model. Biochim Biophys Acta. 2001 Nov 7;1568(1):60-6 Yu FX, Lin SC, Morrison-Bogorad M, Atkinson MA, Yin HL. Thymosin beta 10 and thymosin beta 4 are both actin monomer sequestering proteins. J Biol Chem. 1993 Jan 5;268(1):502-9 Lee SH, Zhang W, Choi JJ, Cho YS, Oh SH, Kim JW, Hu L, Xu J, Liu J, Lee JH. Overexpression of the thymosin beta-10 gene in human ovarian cancer cells disrupts F-actin stress fiber and leads to apoptosis. Oncogene. 2001 Oct 11;20(46):6700-6 Hall AK. Amplification-independent overexpression of thymosin beta-10 mRNA in human renal cell carcinoma. Ren Fail. 1994;16(2):243-54 Vasile E, Tomita Y, Brown LF, Kocher O, Dvorak HF. Differential expression of thymosin beta-10 by early passage and senescent vascular endothelium is modulated by VPF/VEGF: evidence for senescent endothelial cells in vivo at sites of atherosclerosis. FASEB J. 2001 Feb;15(2):458-66 Yu FX, Lin SC, Morrison-Bogorad M, Yin HL. Effects of thymosin beta 4 and thymosin beta 10 on actin structures in living cells. Cell Motil Cytoskeleton. 1994;27(1):13-25 Gómez-Márquez J, Anadón R. The beta-thymosins, small actin-binding peptides widely expressed in the developing and adult cerebellum. Cerebellum. 2002 Apr;1(2):95-102 Hall AK. Thymosin beta-10 accelerates apoptosis. Cell Mol Biol Res. 1995;41(3):167-80 Gutiérrez-Pabello JA, McMurray DN, Adams LG. Upregulation of thymosin beta-10 by Mycobacterium bovis infection of bovine macrophages is associated with apoptosis. 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J Biol Chem. 2005 Oct 7;280(40):34003-7 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1169 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review TYMP (thymidine phosphorylase) Irene V Bijnsdorp, Godefridus J Peters Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands (IVB, GJP) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/TYMPID40397ch22q13.html DOI: 10.4267/2042/44924 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology is involved in nucleotide synthesis and thymidine phosphorolysis. Identity Other names: ECGF1, PDECGF, TP HGNC (Hugo): TYMP Location: 22q13.33 hPD-ECGF, MNGIE, Description Thymidine phosphorylase is located at chromosome 22 in the region of q13.33. cDNA is approximately 1.8 kb long, consisting of 10 exons in a 4.3 kb region (Hagiwara et al., 1991; Stenman et al., 1992). TP was first cloned and sequenced in 1989 (Ishikawa et al., 1989). The nucleic acid sequence of TP is highly conserved, the human TP shares 39% sequence identity with that of E. coli (Barton et al., 1992). DNA/RNA Note The TP gene encodes an angiogenic factor which promotes angiogenesis both in vitro and in vivo and TYMP is located on chromosome 22 of which 3 transcripts have been identified. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1170 TYMP (thymidine phosphorylase) Bijnsdorp IV, Peters GJ pyrimidine nucleoside to another pyrimidine base. Subsequently a new pyrimidine nucleoside is formed. The sugars that are formed by degradation of thymidine are thought to play a role in the induction of angiogenesis. Deoxyribose-1-P can be converted to deoxyribose-5-phosphate or degraded to deoxyribose. Deoxyribose can be secreted, and possibly attract endothelial cells to form new blood vessels (reviewed in de Bruin et al., 2006; Liekens et al., 2007; Bronckaers et al., 2009). TP in some cancer cells can also increase their invasive potential, although the exact mechanism remains unclear. TP can also activate or inactivate several pyrimidines or pyrimidine nucleoside analogs with antiviral and antitumoral activity, such as inactivation of trifluorothymidine (TFT) (Heidelberger et al., 1964) and 5-fluoro-2'-deoxyruidine (van Laar et al., 1998), or activation of 5-fluorouracil (5-FU) (Schwartz et al., 1995) and 5-fluoro-5'-deoxyuridine (5'DFUR). Transcription The promoter region of the TP gene has no TATA box or CCAAT box, but has a high G-C content and seven copies of the SP-1 binding site upstream from the transcription start site. Exact TP gene regulation is unknown, but has been described to be (indirectly) regulated by NFkB, TNFalpha and IFN-gamma (Waguri et al., 1997; Zhu et al., 2002; Zhu et al., 2003; Eda et al., 1993; de Bruin et al., 2004). Protein Note Thymidine phosphorylase was first identified as the platelet-derived endothelial cell growth factor, because it was related to endothelial cell growth (Miyazono et al., 1987; Ishikawa et al., 1989). Later on, it was found that it was identical to thymidine phosphorylase (Furukawa et al., 1992). Thymidine phosphorylase (TP) is the most correct name to refer to this protein, since it catalyzes the phopshorolysis of thymidine to thymine. TP undergoes limited post-translational modification and is not glycosylated. Covalent linkage between serine residues of TP and phosphate groups of nucleotides has been observed, which may facilitate secretion of the protein (Usuki et al., 1991). However, TP does not contain a classical secretion signal (Ishikawa et al., 1989). TP is a dimer, consisting of two identical subunits that are non-covalently associated (Desgranges et al., 1981) with its dimeric molecular mass ranging from 90 kD in Escherichia coli to 110 kD in mammals (Schwartz, 1978; Desgranges et al., 1981). Homology The TYMP gene is conserved in chimpanzee, mouse, rat, and zebrafish. Mutations Note Mutations in this gene have been associated with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Multiple alternatively spliced variants, encoding the same protein, have been identified. Implicated in Description Various cancer TP protein does not contain a known receptor binding region or a secretion signal (Ishikawa et al., 1989). It is implicated in nucleotide synthesis and degradation of thymidine. TP is also implicated in angiogenesis (reviewed in de Bruin et al., 2006; Liekens et al., 2007; Bronckaers et al., 2009). Note TP in tumor sites can be expressed in the cancer cells, in the most malignant cells, tumor stromal cells (such as macrophages) or in the invasive part of the tumor (van Triest et al., 1999). A high TP expression and activity have been related to a poor outcome and increased angiogenesis. The TP gene is regulated by many other factors that are implicated in cancer, such as NFkB (de Bruin et al., 2004). TP regulates the expression of IL-8, and possibly also that of other genes, although the exact mechanism of this regulation is still unclear (Brown et al., 2000; Bijnsdorp et al., 2008). The high TP activity in the tumor can selectively activate the 5FU prodrug 5'-deoxy-5-fluorouridine to 5FU. 5'deoxy-5-fluorouridine is an intermediate of the oral 5FU prodrug Capecitabine (Xeloda) (de Bruin et al., 2006). On the other hand TP can inactivate the fluoropyrimidine trifluorothymidine (TFT), which is registered as the antiviral drug Viroptic® (De Clercq, 2004). An inhibitor of TP, TPI, will prevent inactivation of TFT. TAS-102 is a combination of TFT and TPI (in a molar ratio of 1:0.5) which is developed as an anticancer drug (Temmink et al., 2007). Expression TP is highly expressed in liver tissues. Furthermore, TP is often overexpressed in tumor sites and is involved in inflammatory diseases, such as rheumatoid arthritis. Localisation TP is expressed in the cytoplasm and the nucleus (Fox et al., 1995). Function TP catalyzes the phosphorolysis of thymidine (TdR) to thymine and 2-deoxy-alpha-D-ribose 1-phosphate (dR1-P). TP can also catalyze the formation of thymidine from thymine and dR-1-P. TP also catalyzes the phosphorolysis of deoxyuridine to uracil and dR-1-P. TP also has deoxyribosyl transferase activity by which the deoxyribosyl moiety is transferred from a Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1171 TYMP (thymidine phosphorylase) Bijnsdorp IV, Peters GJ glomeruli) where it probably plays a critical role in the progression of interstitial fibrosis (Wang et al., 2006). Disease Gastrointestinal tumors (Fox et al., 1995; Yoshikawa et al., 1999; Kimura et al., 2002; Takebayashi et al., 1996), breast cancer (Moghaddam et al., 1995), bladder cancer (O'Brien et al., 1996). Prognosis High expression is often related to a poor prognosis, an increased microvessel density and increased metastasis. Abnormal protein No fusion protein has been described. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) Note An autosomal recessive disorder involving DNA alterations (Bardosi et al., 1987). Gene mutations in the TP gene include missense, splice sites microdeletions and single nucleotide insertions (Spinazzola et al., 2002; Nishino et al., 2000). These mutations are associated with a severe reduction in TP activity. This leads to increased thymidine plasma levels, and increased deoxyuridine levels (which is also a substrate for TP). Prognosis Not determined. Rheumatoid arthritis Note Elevated levels of (circulating) PD-ECGF (TP) were found in rheumatoid arthritis patients (Asai et al., 1993). In the sera and synovial fluids of patients suffering from rheumatoid arthritis PD-ECGF (TP) was detected at high levels (Asai et al., 1993). In addition, there was a significant positive correlation between PD-ECGF (TP) levels in synovial fluid and in serum (Asai et al., 1993). The elevated PD-ECGF (TP) levels presumably arise through induction of PD-ECGF (TP) in synoviocytes, resulting from aberrant production of cytokines like TNF-alpha and IL-1 (Waguri et al., 1997). References HEIDELBERGER C, ANDERSON SW. FLUORINATED PYRIMIDINES. XXI. THE TUMOR-INHIBITORY ACTIVITY OF 5-TRIFLUOROMETHYL-2'-DEOXYURIDINE. Cancer Res. 1964 Dec;24:1979-85 Schwartz M. Thymidine phosphorylase from Escherichia coli. Methods Enzymol. 1978;51:442-5 Desgranges C, Razaka G, Rabaud M, Bricaud H. Catabolism of thymidine in human blood platelets: purification and properties of thymidine phosphorylase. Biochim Biophys Acta. 1981 Jul 27;654(2):211-8 Atherosclerosis Note TP is expressed in atherosclerosis. Macrophages, foam cells and giant cells from both aortic and coronary plaques expressed TP, suggesting that TP may play a role in the pathogenesis of atherosclerosis (Boyle et al., 2000). Bardosi A, Creutzfeldt W, DiMauro S, Felgenhauer K, Friede RL, Goebel HH, Kohlschütter A, Mayer G, Rahlf G, Servidei S. Myo-, neuro-, gastrointestinal encephalopathy (MNGIE syndrome) due to partial deficiency of cytochrome-c-oxidase. A new mitochondrial multisystem disorder. Acta Neuropathol. 1987;74(3):248-58 Psoriasis Miyazono K, Okabe T, Urabe A, Takaku F, Heldin CH. Purification and properties of an endothelial cell growth factor from human platelets. J Biol Chem. 1987 Mar 25;262(9):4098103 Note Increased PD-ECGF (TP) mRNA and immunoreactivity were found in lesional psoriasis compared to the non-lesional skin (Creamer et al., 1997). In another study it was reported that the thymidine phosphorylase activity was twenty-fold higher in psoriatic lesions than in normal skin (Hammerberg et al., 1991). Ishikawa F, Miyazono K, Hellman U, Drexler H, Wernstedt C, Hagiwara K, Usuki K, Takaku F, Risau W, Heldin CH. Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature. 1989 Apr 13;338(6216):557-62 Hagiwara K, Stenman G, Honda H, Sahlin P, Andersson A, Miyazono K, Heldin CH, Ishikawa F, Takaku F. Organization and chromosomal localization of the human platelet-derived endothelial cell growth factor gene. Mol Cell Biol. 1991 Apr;11(4):2125-32 Inflammatory bowel disease Note In inflammatory bowel disease, TP has been found to be overexpressed, predominantly in macrophages and fibroblasts of the inflamed colonic mucosa. The grade of expression augmented with an increasing grade of inflammation. In addition, TP was found in the endothelial cells of the inflamed colonic mucosa (Giatromanolaki et al., 2003; Saito et al., 2003). Hammerberg C, Fisher GJ, Voorhees JJ, Cooper KD. Elevated thymidine phosphorylase activity in psoriatic lesions accounts for the apparent presence of an epidermal "growth inhibitor," but is not in itself growth inhibitory. J Invest Dermatol. 1991 Aug;97(2):286-90 Usuki K, Miyazono K, Heldin CH. Covalent linkage between nucleotides and platelet-derived endothelial cell Chronic glomerulonephritis growth factor. J Biol Chem. 1991 Oct 25;266(30):20525-31 Note TP is upregulated in chronic glomerulonephritis (a renal disease characterized by inflammation of the Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Barton GJ, Ponting CP, Spraggon G, Finnis C, Sleep D. Human platelet-derived endothelial cell growth factor is homologous to Escherichia coli thymidine phosphorylase. Protein Sci. 1992 May;1(5):688-90 1172 TYMP (thymidine phosphorylase) Bijnsdorp IV, Peters GJ Furukawa T, Yoshimura A, Sumizawa T, Haraguchi M, Akiyama S, Fukui K, Ishizawa M, Yamada Y. Angiogenic factor. 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J Biol Chem. 1995 Aug 11;270(32):19073-7 Giatromanolaki A, Sivridis E, Maltezos E, Papazoglou D, Simopoulos C, Gatter KC, Harris AL, Koukourakis MI. Hypoxia inducible factor 1alpha and 2alpha overexpression in inflammatory bowel disease. J Clin Pathol. 2003 Mar;56(3):209-13 O'Brien TS, Fox SB, Dickinson AJ, Turley H, Westwood M, Moghaddam A, Gatter KC, Bicknell R, Harris AL. Expression of the angiogenic factor thymidine phosphorylase/platelet-derived endothelial cell growth factor in primary bladder cancers. Cancer Res. 1996 Oct 15;56(20):4799-804 Saito S, Tsuno NH, Sunami E, Hori N, Kitayama J, Kazama S, Okaji Y, Kawai K, Kanazawa T, Watanabe T, Shibata Y, Nagawa H. Expression of platelet-derived endothelial cell growth factor in inflammatory bowel disease. J Gastroenterol. 2003;38(3):229-37 Takebayashi Y, Yamada K, Miyadera K, Sumizawa T, Furukawa T, Kinoshita F, Aoki D, Okumura H, Yamada Y, Akiyama S, Aikou T. The activity and expression of thymidine phosphorylase in human solid tumours. Eur J Cancer. 1996 Jun;32A(7):1227-32 Zhu GH, Schwartz EL. Expression of the angiogenic factor thymidine phosphorylase in THP-1 monocytes: induction by autocrine tumor necrosis factor-alpha and inhibition by aspirin. Mol Pharmacol. 2003 Nov;64(5):1251-8 Creamer D, Jaggar R, Allen M, Bicknell R, Barker J. Overexpression of the angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase in psoriatic epidermis. Br J Dermatol. 1997 Dec;137(6):851-5 de Bruin M, Peters GJ, Oerlemans R, Assaraf YG, Masterson AJ, Adema AD, Dijkmans BA, Pinedo HM, Jansen G. Sulfasalazine down-regulates the expression of the angiogenic factors platelet-derived endothelial cell growth factor/thymidine phosphorylase and interleukin-8 in human monocyticmacrophage THP1 and U937 cells. Mol Pharmacol. 2004 Oct;66(4):1054-60 Waguri Y, Otsuka T, Sugimura I, Matsui N, Asai K, Moriyama A, Kato T. Gliostatin/platelet-derived endothelial cell growth factor as a clinical marker of rheumatoid arthritis and its regulation in fibroblast-like synoviocytes. Br J Rheumatol. 1997 Mar;36(3):315-21 van Laar JA, Rustum YM, Ackland SP, van Groeningen CJ, Peters GJ. Comparison of 5-fluoro-2'-deoxyuridine with 5fluorouracil and their role in the treatment of colorectal cancer. Eur J Cancer. 1998 Feb;34(3):296-306 De Clercq E. Antiviral drugs in current clinical use. J Clin Virol. 2004 Jun;30(2):115-33 de Bruin M, Temmink OH, Hoekman K, Pinedo H, Peters GJ.. Role of platelet derived endothelial cell growth factor/ thymidine phosphorylase in health and disease. Cancer Therapy. 2006;4:99-124. (REVIEW) Yoshikawa T, Suzuki K, Kobayashi O, Sairenji M, Motohashi H, Tsuburaya A, Nakamura Y, Shimizu A, Yanoma S, Noguchi Y. Thymidine phosphorylase/platelet-derived endothelial cell growth factor is upregulated in advanced solid types of gastric cancer. Br J Cancer. 1999 Mar;79(7-8):1145-50 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Wang EH, Goh YB, Moon IS, Park CH, Lee KH, Kang SH, Kang CS, Choi YJ. Upregulation of thymidine phosphorylase in 1173 TYMP (thymidine phosphorylase) Bijnsdorp IV, Peters GJ chronic glomerulonephritis and its role in tubulointerstitial injury. Nephron Clin Pract. 2006;102(3-4):c133-42 factor/thymidine phosphorylase in tumor behavior. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):681-91 Liekens S, Bronckaers A, Pérez-Pérez MJ, Balzarini J. Targeting platelet-derived endothelial cell growth factor/thymidine phosphorylase for cancer therapy. Biochem Pharmacol. 2007 Dec 3;74(11):1555-67 Bronckaers A, Gago F, Balzarini J, Liekens S. The dual role of thymidine phosphorylase in cancer development and chemotherapy. Med Res Rev. 2009 Nov;29(6):903-53 This article should be referenced as such: Temmink OH, Emura T, de Bruin M, Fukushima M, Peters GJ. Therapeutic potential of the dual-targeted TAS-102 formulation in the treatment of gastrointestinal malignancies. Cancer Sci. 2007 Jun;98(6):779-89 Bijnsdorp IV, Peters GJ. TYMP (thymidine phosphorylase). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):11701174. Bijnsdorp IV, de Bruin M, Laan AC, Fukushima M, Peters GJ. The role of platelet-derived endothelial cell growth Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1174 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review der(6)t(1;6)(q21-23;p21) Adriana Zamecnikova Kuwait Cancer Control Center, Laboratory of Cancer Genetics, Department of Hematology, Shuwaikh, 70653, Kuwait (AZ) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/der6t0106q21p21ID1546.html DOI: 10.4267/2042/44925 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Partial karyotypes showing the chromosomal translocation der(6)t(1;6)(q21-23;p21) identified by G-banding. years old male, progressed to AML. From the known data of 14 patients with myelofibrosis, median age was 65.5 years (range, 38-72 years). Clinics and pathology Disease Clinics Most frequently observed in chronic myeloproliferative disorders, occurs with higher frequency in patients with chronic idiopathic myelofibrosis, polycythemia vera and post-polycythemic myelofibrosis; may be present either at diagnosis or during transformation to advanced stages of the disease. In the largest study, the anomaly was associated with splenomegaly, elevated WBC count, elevated levels of alkaline phosphatase and lactate dehydrogenase; median overall survival was 7.8 years: five patients have died (one transformed to acute myeloid leukemia and the others died because of sepsis or thrombosis). Epidemiology Described in 20 cases (11 males, 9 females): 1 biphenotypic leukemia (16 years old male); 1 B-cell lymphoma (73 years old female); 2 acute myeloid leukemia (AML) patients (1 male 71 years old, 1 female 28 years old); and in 16 patients with myelofibrosis with myeloid metaplasia (9 males; 7 females): eleven patients had myelofibrosis with myeloid metaplasia, three post-polycythemic myeloid metaplasia, and one post-thrombocythemic myeloid metaplasia; one of these patients, a 47 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Cytogenetics Cytogenetics morphological Breakpoints may be controversial and difficult to ascertain in poor quality preparations. Recently, the same breakpoint on 6p21.3 and clustering of breakpoints near the paracentric region 1q21-23 was described in 14 patients with myelofibrosis with myelocytic metaplasia. 1175 der(6)t(1;6)(q21-23;p21) Zamecnikova A the underlying molecular consequences rearrangement remain to be determined. Additional anomalies Sole anomaly in 9 cases (2 AML and 7 cases with myelofibrosis); no recurrent additional anomaly observed in patients with complex karyotypes. 4 patients had two or more different clones (1 patient with biphenotypic leukemia and 3 myelofibrosis cases); among them 2 patients had 1q21-23 rearrangements involving the homologous chromosome 1. the To be noted Case Report der(6)t(1;6)(q21;p21) polycythemia vera. in myelofibrosis following References Result of the chromosomal anomaly Mertens F, Johansson B, Heim S, Kristoffersson U, Mitelman F. Karyotypic patterns in chronic myeloproliferative disorders: report on 74 cases and review of the literature. Leukemia. 1991 Mar;5(3):214-20 Fusion protein Reilly JT, Snowden JA, Spearing RL, Fitzgerald PM, Jones N, Watmore A, Potter A. Cytogenetic abnormalities and their prognostic significance in idiopathic myelofibrosis: a study of 106 cases. Br J Haematol. 1997 Jul;98(1):96-102 Oncogenesis The presence of the der(6)t(1;6) results in partial trisomy for 1q21-23 to 1qter and in loss of 6p21 to 6pter. The pathogenetic significance may be the consequence of gain of gene(s) on 1q and/or haploinsufficiency of gene(s) from 6p and alternatively, rearrangements of one or more genes at the breakpoints. The significance of the 6p21 breakpoint is unclear; however a number of published reports of myelofibrosis with chromosome 6p breakpoints in the region raise the possibility of a gene involved in the pathogenesis of this hematologic disorder. The inability to identify common breakpoints on 1q, suggests that an increase in gene copy number is a pathogenetic event. Whether trisomy 1q is a secondary event to a primary (cryptic? e.g. JAK2 V617F mutation) anomaly as well as the roles of methylation, cytotoxic treatments and Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) of Andrieux J, Demory JL, Caulier MT, Agape P, Wetterwald M, Bauters F, Laï JL. Karyotypic abnormalities in myelofibrosis following polycythemia vera. Cancer Genet Cytogenet. 2003 Jan 15;140(2):118-23 Dingli D, Grand FH, Mahaffey V, Spurbeck J, Ross FM, Watmore AE, Reilly JT, Cross NC, Dewald GW, Tefferi A. Der(6)t(1;6)(q21-23;p21.3): a specific cytogenetic abnormality in myelofibrosis with myeloid metaplasia. Br J Haematol. 2005 Jul;130(2):229-32 Hussein K, Van Dyke DL, Tefferi A. Conventional cytogenetics in myelofibrosis: literature review and discussion. Eur J Haematol. 2009 May;82(5):329-38 This article should be referenced as such: Zamecnikova A. der(6)t(1;6)(q21-23;p21). Atlas Cytogenet Oncol Haematol. 2010; 14(12):1175-1176. 1176 Genet Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication ins(9;4)(q33;q12q25) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/ins0904q33q12q25ID1450.html DOI: 10.4267/2042/44926 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology assembly (Fong et al., 2009); critical for centrosomal localization of dynein throughout the cell cycle (Lee and Rhee, 2010). CDK5RAP2-knockdown cells have increased resistance to paclitaxel and doxorubicin (Zhang et al., 2009). Homozygous mutations in CDK5RAP2 can cause microcephaly (Bond et al., 2005). Clinics and pathology Disease Chronic eosinophilic leukemia Epidemiology One case to date, a 71-year-old female patient with chronic eosinophilic leukemia in accelerated phase (Walz et al., 2006). Result of the chromosomal anomaly Prognosis Remission was obtained with imatinib, but the patient relapsed with imatinib-resistant acute myeloid leukemia that was characterized by a normal karyotype, absence of detectable CDK5RAP2-PDGFRA mRNA, and a newly acquired G12D NRAS mutation. Hybrid gene Description In-frame fusion between exon 13 of the CDK5RAP2, a 40 bp insert from an inverted sequence of PDGFRA intron 9, and a truncated PDGFRA exon 12. No reciprocal PDGFRA-CDK5RAP2 transcript. Genes involved and proteins Fusion protein PDGFRA Description N-term CDK5RAP2 - C-term PDGFRA; 1003 amino acids; contains 494 amino acids, including several potential dimerization domains, of CDK5RAP2 and 509 amino acids from PDGFRA tyrosine kinase domains. Oncogenesis Constitutive tyrosine kinase activity is likely. Location 4q25 Protein Receptor tyrosine kinase. Gain-of-function mutations of PDGFRA are implicated in a subset of gastrointestinal stromal tumors (Heinrich et al., 2003). PDGFRA has also been involved in translocations, making hybrid genes with STRN (2p22), FIP1L1 (4q12), KIF5B (10p11), ETV6 (12p13) and BCR (22q11). References Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003 Jan 31;299(5607):708-10 CDK5RAP2 Location 9q33 Protein Centrosomal protein; regulates CDK5; binds EB1. The CDK5RAP2-EB1 complex stimulates microtubule Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Bond J, Roberts E, Springell K, Lizarraga SB, Scott S, Higgins J, Hampshire DJ, Morrison EE, Leal GF, Silva EO, Costa SM, Baralle D, Raponi M, Karbani G, Rashid Y, Jafri H, Bennett C, 1177 ins(9;4)(q33;q12q25) Huret JL Corry P, Walsh CA, Woods CG. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat Genet. 2005 Apr;37(4):353-5 Fong KW, Hau SY, Kho YS, Jia Y, He L, Qi RZ. Interaction of CDK5RAP2 with EB1 to track growing microtubule tips and to regulate microtubule dynamics. Mol Biol Cell. 2009 Aug;20(16):3660-70 Walz C, Curtis C, Schnittger S, Schultheis B, Metzgeroth G, Schoch C, Lengfelder E, Erben P, Müller MC, Haferlach T, Hochhaus A, Hehlmann R, Cross NC, Reiter A. Transient response to imatinib in a chronic eosinophilic leukemia associated with ins(9;4)(q33;q12q25) and a CDK5RAP2PDGFRA fusion gene. Genes Chromosomes Cancer. 2006 Oct;45(10):950-6 Zhang X, Liu D, Lv S, Wang H, Zhong X, Liu B, Wang B, Liao J, Li J, Pfeifer GP, Xu X. CDK5RAP2 is required for spindle checkpoint function. Cell Cycle. 2009 Apr 15;8(8):1206-16 Lee S, Rhee K. CEP215 is involved in the dynein-dependent accumulation of pericentriolar matrix proteins for spindle pole formation. Cell Cycle. 2010 Feb 15;9(4):774-83 Gotlib J, Cools J. Five years since the discovery of FIP1L1PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias. Leukemia. 2008 Nov;22(11):1999-2010 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) This article should be referenced as such: Huret JL. ins(9;4)(q33;q12q25). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1177-1178. 1178 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Solid Tumour Section Short Communication t(19;22)(q13;q12) in myoepithelial carcinoma Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2010 Online updated version : http://AtlasGeneticsOncology.org/Tumors/t1922q13q12MyoCarcID6287.html DOI: 10.4267/2042/44927 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Clinics and pathology Genes involved and proteins Disease ZNF444 Myoepithelioma tumours of soft tissue cover a wide range of tumours of various behaviour. While most are of intermediate aggressivity, some metastasize. There is no sex ratio predominance. Mean age at diagnosis is 38 years; with a range of 3-83 years. Of a hundred of cases reviewed by Hornick and Fletcher (2003), 60% were benign and classified as myoepitheliomas or mixed tumors, and 40% were classified as myoepithelial carcinomas or malignant mixed tumours. Amongst cases with benign or low-grade cytology, with a mean follow-up of 3 years, 20% recurred locally and none metastasized. Amongst cytologically malignant cases, with a mean follow-up of 4 years, 40% recurred locally, 1/3 metastasized, and 4 out of 31 patients died. Tumours are positive for epithelial markers, and for S100 or GFAP, or myogenic markers (Gleason and Fletcher, 2007). Location 19q13 Protein Possess a SCAN domain and 4 C2H2-type zinc fingers. Transcription factor. Epidemiology Result of the chromosomal anomaly EWSR1 Location 22q12 Protein From N-term to C-term: a transactivation domain (TAD) containing multiple degenerate hexapeptide repeats, 3 arginine/glycine rich domains (RGG regions), a RNA recognition motif, and a RanBP2 type Zinc finger. Role in transcriptional regulation for specific genes and in mRNA splicing. One case to date, a 40-year-old female patient. After surgical removal, recurrences occured during 2 years, and metastases appeared 3 years later. The patient finally died 9.5 years after initial diagnosis (Brandal et al., 2009). Hybrid Gene Description 5' EWSR1 - 3' ZNF444; fuses EWSR1 exon 8 to the very near end of ZNF444 (at nucleotide 967, while the full transcript of ZNF444 is 984 nt long!). Cytogenetics Cytogenetics Morphological Fusion Protein The t(19;22)(q13;q12) was found within a complex karyotype. Description Truncated EWSR1 with 6 amino acids added from Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1179 t(19;22)(q13;q12) in myoepithelial carcinoma Huret JL Gleason BC, Fletcher CD. Myoepithelial carcinoma of soft tissue in children: an aggressive neoplasm analyzed in a series of 29 cases. Am J Surg Pathol. 2007 Dec;31(12):1813-24 ZNF444. This does not fit with the usual model of carcinogenesis found with other EWSR1 translocations, were there is fusion of the N terminal transactivation domain of EWSR1 to the DNA binding domain of the partner (e.g. FLI1). Brandal P, Panagopoulos I, Bjerkehagen B, Heim S. t(19;22)(q13;q12) Translocation leading to the novel fusion gene EWSR1-ZNF444 in soft tissue myoepithelial carcinoma. Genes Chromosomes Cancer. 2009 Dec;48(12):1051-6 References This article should be referenced as such: Hornick JL, Fletcher CD. Myoepithelial tumors of soft tissue: a clinicopathologic and immunohistochemical study of 101 cases with evaluation of prognostic parameters. Am J Surg Pathol. 2003 Sep;27(9):1183-96 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Huret JL. t(19;22)(q13;q12) in myoepithelial carcinoma. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1179-1180. 1180 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Deep Insight Section Glutathione S-Transferase pi (GSTP1) Isabelle Meiers Maidstone and Tunbridge Wells NHS Trust, Preston Hall Hospital, Royal British Legion Village, Aylesford, Kent, ME20 7NJ, UK (IM) Published in Atlas Database: February 2010 Online updated version : http://AtlasGeneticsOncology.org/Deep/GSTP1inCancerID20084.html DOI: 10.4267/2042/44928 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology the glutathione S-transferase family enzymes that inactivates electrophilic carcinogens by conjugation with glutathione (Toffoli et al., 1992; Jerónimo et al., 2001). The regulatory sequence near the GST gene is commonly affected by hypermethylation during the early stages of carcinogenesis (Lee et al., 1994; Brooks et al., 1998; Cairns et al., 2001; Jerónimo et al., 2002; Henrique and Jerónimo, 2004). Several classes of GST, including alpha, mu, pi, and theta, were previously found in human tissue. For example, compared with benign tissue, there is increased expression of GST pi in cancers of the breast, colon, stomach, pancreas, bladder, lung, head and neck, ovary, and cervix, as well as soft tissue sarcoma, testicular embryonal carcinoma, meningioma, and glioma (Niitsu et al., 1989; Randall et al., 1990; Kantor et al., 1991; Satta et al., 1992; Toffoli et al., 1992; Green et al., 1993; Inoue et al., 1995; Bentz et al., 2000; Tratche et al., 2002; Simic et al., 2005; Arai et al., 2006). However, hypermethylation of the GSTP1 promoter has been associated with gene silencing in prostate cancer and kidney cancer (Lee et al., 1994; Brooks et al., 1998; Cairns et al., 2001; Jerónimo et al., 2002; Dulaimi et al., 2004). Similarly, expression of GSTP1 is lower in invasive pituitary tumors than in noninvasive pituitary tumors and methylation status correlates with significant downregulation of GSTP1 expression; the frequency of GSTP1 methylation being higher in invasive pituitary tumors with reducedGSTP1 expression than in pituitary adenomas with normal or high GSTP1 expression. These data indicate that GSTP1 inactivation through CpG hypermethylation is common in pituitary adenomas and may contribute to aggressive pituitary tumor behavior (Yuan et al., 2008). More recently, a study showed a trend of increasing GSTP1 methylation frequency with increasing grade of mammary phyllodes tumors. The Running title: GSTP1 review Key words: Glutathione S-transferase pi (GSTP1), cancer, methylation analysis, antioxidants. Pi-class glutathione-S-transferase (GSTP1) located on chromosome 11q13 encodes a phase II metabolic enzyme that detoxifies reactive electrophilic intermediates. GSTP1 plays an important role in protecting cells from cytotoxic and carcinogenic agents and is expressed in normal tissues at variable levels in different cell types. Altered GSTP1 activity and expression have been reported in many tumors and this is largely due to GSTP1 DNA hypermethylation at the CpG island in the promoter-5'. We review the potential novel role of glutathione Stransferase pi (GSTP1) and its related expression in miscellaneous cancers. We focus on the rationale for use of molecular assays for the detection of cancer, emphasizing the role of the identification of epigenetic alterations. Finally, we focus on the potential role of GSTP1 in the pathway of prostate cancer, the most GSTP1 DNA hypermethylation-related neoplasm studied to date. Advances in the epigenetic characterization of cancers enabled the development of DNA methylation assays that may soon be used in diagnostic testing of serum and tissue for cancers. Inhibition of aberrant promoter methylation could theoretically prevent carcinogenesis. Reactive oxygen species that are generated by physiologic processes such as cellular respiration, exposure to chemical agents, or exposure to ionizing radiation may overcome cellular antioxidant defense and cause DNA damage (Bostwick et al., 2000). Such damage may result in mutations and alteration of oncogenes or tumor suppressor genes. The cytosolic isoenzyme glutathione S-transferase pi (GSTP1) is an important multifunctional detoxifying enzyme within Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1181 Glutathione S-Transferase pi (GSTP1) Meiers I authors reported that GSTP1 promoter hypermethylation was associated with loss of GSTP1 expression. These results suggest that phyllodes tumors segregate into only two groups on the basis of their methylation profiles: the benign group and the combined borderline/malignant group (Kim et al., 2009). Other investigators studied the role of hypermethylation of the GSTP1 gene promoter region in endometrial carcinoma and found that reduced GSTP1 expression was associated with myometrial invasion potential (Chan et al., 2005). allowing quantitation or identification of partial methylation. The CMSP assay is mainly used for GSTP1 methylation detection in fluids. For instance, GSTP1 methylation in serum of men with localized prostate cancer prior to treatment carries a 4.4 fold increased risk of biochemical recurrence following surgery (Bastian et al., 2005). The use of fluorescence-based real-time quantitative methylation-specific PCR (QMSP) assay improved the sensitivity of tumor detection. Continuous monitoring of fluorescent signals during the PCR process enabled quantification of methylated alleles of a single region amongst unmethylated DNA because the fluorescence emission of the reporter represents the number of generated DNA fragments (Heid et al., 1996). Epigenetic alterations: emerging molecular markers for cancer detection Cancer is a process fuelled both by genetic alterations and epigenetic mechanisms. Epigenetics refer to changes in gene expression that can be mitotically inherited, but are not associated with the changes in the coding sequence of the affected genes. In other words, epigenetics refer to the inheritance of information based on gene expression levels, in contrast to genetics that refer to transmission of information based on gene sequence (Esteller et al., 2000). DNA methylation, the best understood mechanism in epigenetics, is an enzyme-mediated chemical modification that adds methyl (-CH3) groups at selected sites on DNA. In humans and most mammals, DNA methylation only affects the cytosine base (C), when it is followed by a guanosine (G). Methylation of the cytosine nucleotide residue located within the dinucleotide 5'-CpG-3' is the most frequent epigenetic alteration in humans. These CpG dinucleotides are not randomly distributed in the genome. Indeed, there are CpG-rich regions called "CpG islands" frequently associated with the 5' regulatory regions of genes, including the promoter. DNA methylation in the promoter regions is a powerful mechanism for the suppression of gene activity. GSTP1 hypermethylation: significance and incidence related to prostate cancer Epigenetic silencing of gluthathione-S-transferase pi (GSTP1) is recognized as being a molecular hallmark of human prostate cancer. Methylation of CpG islands in the promoter of the pi class of glutathione Stransferase occurs in prostatic intraepithelial neoplasia (PIN) and cancer (Gonzalgo et al., 2004). Other hypermethylated regions relevant to prostate cancer include the retinoic acid receptor beta 2 (Bastian et al., 2007). These findings in prostate cancer suggest that DNA methylation is among the early events in tumorigenesis, but it remains to be seen whether DNA methylation is a necessary or permissive event in tumorigenesis. The extensive methylation of deoxycytidine nucleotides distributed throughout the 5' "CG island" region of GSTP1 is not detected in benign prostatic epithelium, but has been detected in intraepithelial neoplasia, prostatic adenocarcinoma, and fluids (plasma, serum, ejaculate, and urine) of patients with prostate cancer by methylation-specific polymerase chain reaction assay, and may be useful as a cancerspecific molecular biomarker (Lee et al., 1994; Cairns et al., 2001; Henrique and Jerónimo, 2004; Crocitto et al., 2004; Perry et al., 2006; Hopkins et al., 2007; Cao and Yao, 2010). Quantitative methylation-specific PCR (QMSP) reveals that the epigenetic silencing (loss of expression) of the GSTP1 gene is in fact the most common genetic alteration in prostate cancer (>90%) and high-grade prostatic intraepithelial neoplasia (PIN) (70%) (Lee et al., 1994; Brooks et al., 1998; Cairns et al., 2001; Harden et al., 2003; Henrique and Jerónimo, 2004) and this somatic inactivation ("silencing") of GSTP1 is directly associated with promoter methylation (Cairns et al., 2001; Jerónimo et al., 2002; Henrique and Jerónimo, 2004). Higher levels of GSTP1 promoter methylation is associated with the transition from prostatic intraepithelial neoplasia (PIN) to carcinoma (Henrique et al., 2006). During cancer development, GSTP1 does not appear to function either as an oncogene or as a tumor suppressor DNA methylation analysis: currently available methods Methylation of CpG islands is of interest for diagnostic and prognostic reasons. Methylation of one or both alleles of a region can serve as a biomarker of cancer or silence gene expression when they are in a promoter region (Verma and Srivastava, 2002). Assays for methylation are appealing for translational research since they can utilize amplification techniques, such as methylation-specific polymerase chain reaction (PCR), and thereby utilize small amounts of samples. Due to its relative simplicity, safety, and sensitivity, methylation-specific PCR is the most commonly employed method for methylation analysis (Herman et al., 1996). The conventional methylation-specific PCR (CMSP) assay uses two sets of primers specifically designed to amplify the methylated or unmethylated sequence, and the PCR products are run in a gel (Herman et al., 1996). The results of CMSP at a particular DNA region are simply reported as methylated or unmethylated, not Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1182 Glutathione S-Transferase pi (GSTP1) Meiers I gene, since induced GSTP1 expression in prostate cancer cell lines failed to suppress cell growth. Instead, GSTP1 was proposed to act as a "caretaker" gene. When GSTP1 is inactivated, prostate cells appear to become more vulnerable to somatic alterations upon chronic exposure to genome-damaging stresses as oxidants and electrophiles, that are contributed by environment and lifestyle (Kinzler and Vogelstein, 1997; Cairns et al., 2001). The significance of absent GSTP1 (GSTP1 silencing) in high grade PIN and carcinoma is unclear. It may be an epiphenomenon, simply reflecting disruption of the basal cell layer with neoplastic progression. However, Lee et al. considered the likelihood of a more fundamental role (Lee et al., 1994). Two studies found that a small proportion (3.5-5%) of cases retained modest GSTP1 expression in carcinoma (Cookson et al., 1997; Moskaluk et al., 1997). Cookson et al. also recorded positivity in 1 of 17 cases of high grade PIN (Cookson et al., 1997) . Unlike genetic alterations that permanently and definitively change DNA sequence, promoter methylation is a potentially reversible modification. Hence, promoter methylation may be amenable to therapeutic intervention aimed at reactivating silenced cancer genes. This has important implications for chemoprevention because, as mentioned above, up to 70% of cases of high-grade PIN display GSTP1 promoter methylation (Brooks et al., 1998; Cairns et al., 2001; Jerónimo et al., 2002). Indeed, recently some authors have investigated the effects of green tea polyphenols (GTPs) on GSTP1 reexpression. They demonstrated that promoter demethylation by green tea polyphenols leads to reexpression of GSTP1 in human prostate cancer cells, therefore making green tea polyphenols excellent candidates for the chemoprevention of prostate cancer (Pandey et al., 2009). Some investigators evaluated the impact of androgen deprivation therapy on the detection of GSTP1 hypermethylation in prostate cancer (Kollermann et al., 2006). In 87% (13/15) of the patients, there was no alteration in GSTP1 hypermethylation detection (Kollermann et al., 2006) and the authors suggested that the change from positive to negative GSTP1 hypermethylation status in two patients may point to partial androgen dependency (Kollermann et al., 2006). In addition to the supposed hormonal interaction, other possible explanations may be speculated to explain why prostate cancer loses GSTP1 hypermethylation after prolonged neoadjuvant hormonal therapy. First, the lack of GSTP1 hypermethylation may be attributable to technical problems (false negative results). Furthermore, the possibility that both tumors primarily lacked GSTP1 hypermethylation might be raised. However, further studies are necessary to assess the frequency and extent of hormonal interaction with GSTP1 hypermethylation. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Anti-cancer effect of GSTP1 and future prospects Increased levels of GST pi may protect human cancer cells against cytotoxic drugs. Several antineoplastic drugs, particularly reactive electrophilic alkylating agents, form conjugates with glutathione spontaneously and in GST-catalyzed reactions (Awasthi et al., 1996). The expression of particular subclasses of GST protects cells from the cytotoxicities of these cancer drugs, and overexpression of GST has been implicated in antineoplastic drug resistance (Morrow et al., 1998). Induction of the enzymes is thought to represent an adaptive response to stress, and may be triggered by exogenous chemical agents and probably also by reactive oxygen metabolites (Hayes and Pulford, 1995). GST enzymes have a broad substrate specificity that includes substances with known mutagenic properties. Elevated serum GST pi has been exploited as a serum tumor marker for gastrointestinal cancer (Niitsu et al., 1989) and non-Hodgkin's lymphoma (Katahira et al., 2004) as a method of predicting sensitivity to chemotherapy. Inactivation of GSTP1 in prostate cancer occurs early during carcinogenesis, leaving prostate cells with inadequate defenses against oxidant and electrophile carcinogens. Epigenetic mechanisms (see above) are strongly implicated in progression (Rennie and Nelson, 1998). Unlike genetic alterations, changes in DNA methylation are potentially reversible. Thus, therapeutic interventions involving reversal of the methylation process of several key genes in prostate carcinogenesis might improve current therapeutic options, thereby enhancing the anti-cancer effect of GSTP1 gene in patients "at risk" with high-grade PIN or in men with established prostate cancer. Nucleosideanalogue inhibitors of DNA methyltransferases, such as 5-aza-2'-deoxycytidine, are able to demethylate DNA and restore silenced gene expression. Unfortunately, the clinical utility of these compounds has not yet been fully realized, mainly because of their side effects. The anti-arrhythmia drug procainamide, a nonnucleoside inhibitor of DNA methyltransferases (category of enzymes that catalyse DNA methylation during cell replication), reversed GSTP1 DNA hypermethylation and restorted GSTP1 expression in LNCaP human prostate cancer cells propagated in vitro or in vivo as xenograft tumors in athymic nude mice (Cairns et al., 2001). Some investigators tested the potential use of procaine, an anesthetic drug related to procainamide. Using the MCF-7 breast cancer cell line, they have found that procaine produced a 40% reduction in 5methylcytosine DNA content as determined by highperformance capillary electrophoresis and total DNA enzyme digestion. Procaine can also demethylate densely hypermethylated CpG islands such as those located in the promoter region of the RAR beta 2 gene, 1183 Glutathione S-Transferase pi (GSTP1) Meiers I Lee WH, Morton RA, Epstein JI, Brooks JD, Campbell PA, Bova GS, Hsieh WS, Isaacs WB, Nelson WG. Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11733-7 restoring gene expression of epigenetically silenced genes. This property may be explained by binding of procaine to CpG-enriched DNA. Finally, procaine also has growth-inhibitory effects in these cancer cells, causing mitotic arrest (Villar-Garea et al., 2003). Thus, procaine and procainamide are promising candidate agents for future cancer therapies based on epigenetics. Li et al. reported that GSTP1 was upregulated in the stromal compartment of hormone-independent prostate cancer, which may contribute to chemoresistance of advanced prostate cancer (Morrow et al., 1998). Epidemiologic evidence has shown a reduced risk of prostate cancer in men consuming selenium, suggesting a role for antioxidants in protection against prostate carcinogenesis. A systematic review and meta-analysis of the literature confirm that selenium intake may reduce the risk of prostate cancer (Etminan et al., 2005). Vitamin E intake also may decrease DNA damage and inhibit transformation through its antioxidant function. Long-term supplementation with alpha-tocopherol substantially reduced prostate cancer incidence and mortality in male smokers (Heinonen et al., 1998). Therapy directed at the induction or preservation of GSTP1 activity in benign prostatic epithelium may prevent or delay progression of prostatic cancer. GSTP1 has a protective role as an antioxidant agent in transformation and progression of prostate cancer. The interplay between altered or impaired expression of GST appears to play a significant role in carcinogenesis in the prostate. Inhibition of aberrant promoter methylation could be an effective method of chemoprevention. Hayes JD, Pulford DJ. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol. 1995;30(6):445-600 Inoue T, Ishida T, Sugio K, Maehara Y, Sugimachi K. 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Intake of selenium in the prevention of prostate cancer: a systematic review and meta-analysis. Cancer Causes Control. 2005 Nov;16(9):1125-31 Jerónimo C, Usadel H, Henrique R, Oliveira J, Lopes C, Nelson WG, Sidransky D. Quantitation of GSTP1 methylation in non-neoplastic prostatic tissue and organ-confined prostate adenocarcinoma. J Natl Cancer Inst. 2001 Nov 21;93(22):1747-52 Simic T, Mimic-Oka J, Savic-Radojevic A, Opacic M, Pljesa M, Dragicevic D, Djokic M, Radosavljevic R. Glutathione Stransferase T1-1 activity upregulated in transitional cell carcinoma of urinary bladder. Urology. 2005 May;65(5):103540 Jerónimo C, Usadel H, Henrique R, Silva C, Oliveira J, Lopes C, Sidransky D. Quantitative GSTP1 hypermethylation in bodily fluids of patients with prostate cancer. Urology. 2002 Dec;60(6):1131-5 Arai T, Miyoshi Y, Kim SJ, Taguchi T, Tamaki Y, Noguchi S. Association of GSTP1 CpG islands hypermethylation with poor prognosis in human breast cancers. 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Borderline and malignant phyllodes tumors display similar promoter methylation profiles. Virchows Arch. 2009 Dec;455(6):469-75 Henrique R, Jerónimo C. Molecular detection of prostate cancer: a role for GSTP1 hypermethylation. Eur Urol. 2004 Nov;46(5):660-9; discussion 669 Cao DL, Yao XD. Advances in biomarkers for the early diagnosis of prostate cancer. Chin J Cancer. 2010 Feb;29(2):229-33 Katahira T, Takayama T, Miyanishi K, Hayashi T, Ikeda T, Takahashi Y, Takimoto R, Matsunaga T, Kato J, Niitsu Y. Plasma glutathione S-Transferase P1-1 as a prognostic factor in patients with advanced non-Hodgkin's lymphoma (stages III and IV). Clin Cancer Res. 2004 Dec 1;10(23):7934-40 Pandey M, Shukla S, Gupta S. Promoter demethylation and chromatin remodeling by green tea polyphenols leads to reexpression of GSTP1 in human prostate cancer cells. Int J Cancer. 2010 Jun 1;126(11):2520-33 Bastian PJ, Palapattu GS, Lin X, Yegnasubramanian S, Mangold LA, Trock B, Eisenberger MA, Partin AW, Nelson WG. Preoperative serum DNA GSTP1 CpG island hypermethylation and the risk of early prostate-specific antigen recurrence following radical prostatectomy. Clin Cancer Res. 2005 Jun 1;11(11):4037-43 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) This article should be referenced as such: Meiers I. Glutathione S-Transferase pi (GSTP1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1181-1185. 1185 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Deep Insight Section The roles of SRA1 gene in breast cancer Yi Yan, Charlton Cooper, Etienne Leygue Manitoba Institute of Cell Biology, University of Manitoba, 770 Bannatyne Avenue, R3E0W3, Winnipeg, Manitoba, Canada (YY, EL); Department of Biochemistry and Medical Genetics, University of Manitoba, 770 Bannatyne Avenue, R3E0W3, Winnipeg, Manitoba, Canada (YY, CC, EL) Published in Atlas Database: March 2010 Online updated version : http://AtlasGeneticsOncology.org/Deep/SRA1inCancerID20085.html DOI: 10.4267/2042/44929 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract The Steroid receptor RNA activator (SRA) gene has been implicated in estrogen receptor signaling pathway. First identified as a RNA coregulator, SRA had been shown to increase steroid receptor activity. SRA RNA expression is altered during breast tumorigenesis and its molecular role in underscoring these events has been suggested. The subsequent identification of molecules capable of binding SRA, including RNA helicase p68, SRA stem-loop interacting RNA binding protein (SLIRP), and steroidogenic factor 1 (SF1) indicates SRA function is not exclusively limited to modulate steroid receptor activity. A recent genome-wide expression analysis by depleting SRA in cancer cells has further expanded our understanding of a broader biological role played by SRA. In addition, several RNA isoforms have been found to encode an endogenous protein (SRAP), which is well conserved among Chordata. Interestingly, SRAP also modulates steroid receptor activity and functions as a co-regulator in estrogen receptor signaling. The recent observation that a higher expression of SRAP protein is associated with poorer survival in breast cancer patients treated with tamoxifen, highlights the potential relevance of this protein in cancer. Together, the SRA1 gene encodes both functional RNA and protein (SRAP) products, making it a unique member amongst the growing population of steroid receptor co-regulators. particularly interesting member within this family was identified by Lanz et al. in 1999, as it was found not to act as a protein molecule but as a functional RNA. This nuclear co-regulator was therefore named Steroid receptor RNA activator (SRA) (Lanz et al., 1999). 1. Introduction It is now quite apparent that the end results of Estrogen Receptor (ER) mediated signaling is not simply limited to ER status and/or the presence of its naturally occurring ligand estridiol. In addition to the two known estrogen receptors, ERα and ERβ, ERs-mediated gene transcription also requires transcription co-regulators, which form complexes with estrogen receptors through protein-protein interactions followed by dynamic recruitment to specific gene promoters. Based on the outcomes of their regulations, co-regulators are categorized as either co-activators or co-repressors if they either promote or prevent gene transcription respectively. These complexes regulate the assembly and activity of the transcription initiation complex through chromatin remodeling (McKenna et al., 1999; Jenuwein and Allis, 2001). Since the characterization of the first co-regulator, the steroid receptor co-activator 1 (SRC-1), this list of factors has grown significantly to now include over 300 co-regulators (Lonard and O'Malley, 2007). One Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 2. Steroid Receptor RNA Activator (SRA) 2.1 Discovery of SRA, an RNA Co-activator In order to identify new potential co-regulators interacting with AF-1 domain of the progesterone receptor (PR), Lanz screened a human B-lymphocyte library using AF-1 domain as bait in a yeast-two-hybrid assay (Lanz et al., 1999). They identified a new clone, they called SRA, for steroid receptor RNA activator. This cDNA was unable to encode a protein, but was required for the growth of the yeast colony. Further experiment confirmed that the potential co-activation role of SRA on PR was mediated through a RNA transcript rather than any protein product. 1186 The roles of SRA1 gene in breast cancer Yan Y, et al. 2001; Deblois and Giguère, 2003; Coleman et al., 2004; Klinge et al., 2004). SRA RNA has been shown to co-activate the action of the AF-2 domain of both ERα and ERβ in a ligand-dependent manner on some, but not all estrogen receptor element (ERE) as measure through luciferase reporters assay (Deblois and Giguère, 2003; Coleman et al., 2004). Interestingly, SRA can also enhance AF-1 domain of ERα but not ERβ in a ligand-independent manner (Coleman et al., 2004; Deblois and Giguère, 2003). Overall, data suggest that the action of the two estrogen receptors are differentially regulated by SRA and SRA regulation of a given receptor is also specific of a given ERE sequence (Leygue, 2007). 2.4 Emerging mechanisms of SRA RNA action Several studies have been published discussing the mechanism of SRA RNA action (Leygue, 2007). 2.2 Core sequence of SRA and predicted functional region In the incipient SRA study, a core sequence spanning SRA exon 2 to exon 5 was found to be necessary and sufficient for co-activation function of SRA RNA (Figure 1, Lanz et al., 1999). Several predicted secondary RNA structural motifs are distributed throughout this core sequence, and are believed to form the functional structures that impart SRA activities. Site-directed mutagenesis experiment revealed six secondary structural motifs (STR1, 7, 9, 10, 11, 12) that independently participate in PR co-activation by SRA (Lanz et al., 2002). It was found that silent mutations in both SRT1 and STR7 of SRA could decrease by more than 80% co-activation SRA's function (Lanz et al., 1999). 2.3 Effect of SRA RNA on ERα and ERβ signaling Several research groups have now confirmed that SRA is able to increase estradiol induced gene transcription by both full length ERs subtypes (Watanabe et al., Figure 1. SRA1 genomic structure and core sequence. A) SRA sequences were originally described, differing in their 5' and 3' extremities, but sharing a central core sequence depicted in light blue (Lanz et al., 1999). One sequence has been registered with the NCBI nucleotide database (AF092038). Alignment with chromosome 5q31.3 genomic sequence is provided. Introns and exons are represented by black lines and blue boxes, respectively. B) Schematic profile of the predicted secondary structure of human core SRA RNA. The secondary structure profile of SRA core sequence has been modeled using Mfold software (Zuker, 2003). Detailed structure of STR1, 10, 7 (Lanz et al., 2002) is provided. C) By doing site-directed mutagenesis experiment, six secondary structural motifs (STR1, 9, 10, 7, 11, 12) have been identified to participate in co-activation respectively. Especially, silent mutations in both SRT1 and STR7 of SRA could nullify above 80% SRA co-activation function (Lanz et al., 2002). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1187 The roles of SRA1 gene in breast cancer Yan Y, et al. (Zhao et al., 2004; Xu and Koenig, 2004) as well as the activity of MyoD, a transcription factor involved in skeletal myogenesis (Caretti et al., 2006; Caretti et al., 2007); SF-1 and DAX-1, orphan NRs that plays critical roles in the regulation of sex determination, adrenal development steroidogenesis (Xu et al., 2009). Recently, Foulds et al. investigated the global changes in gene expression by microarray analyses in two human cancer cell lines when SRA RNA was depleted by small interfering RNAs (Foulds et al., 2010). Unexpectedly, only a small subset of direct estrogen receptor-target genes was affected in estradiol-treated MCF-7 cells. However, they found many target genes involved in diverse biological roles such as glucose uptake, cellular signaling, T3 hormone generation were altered upon SRA depletion. This suggests SRA has a much broader upstream biological impact within the cell than simply a corgualtor of ER-signaling. 2.6 SRA RNA expression and relevance to breast cancer Different SRA transcripts, detected by Northern blot, have been observed in normal human tissues (Lanz et al., 1999). SRA seems highly expressed in liver, skeletal muscle, adrenal gland and the pituitary gland, whereas intermediate expression levels are seen in the placenta, lung, kidney and pancreas. Interestingly, brain and other typical steroid-responsive tissues such as prostate, breast, uterus and ovary contained low levels of SRA RNA (Lanz et al., 1999). However, SRA RNA expression, assessed by RT-PCR amplification, is increased during breast and ovarian tumorigenesis (Lanz et al., 2003; Leygue et al., 1999; Hussein-Fikret and Fuller, 2005). Interestingly, SRA over-expression might characterize particular subtypes of lesions among different tumors. Indeed, serous ovarian tumors expressed higher levels of SRA than granulosa cell tumors (Hussein-Fikret and Fuller, 2005). The involvement of SRA in ER action suggests possible SRA role in breast tumor pathology. Indeed, ER-α-positive/PR-negative breast tumors expressed more SRA than ER-α-positive/PR-positive breast tumors (Leygue et al., 1999), whereas Tamoxifensensitive and resistant breast tumors express similar levels (Murphy et al., 2002). However, generation of transgenic mice has however demonstrated that overexpression of the core SRA sequence in the mammary gland only led to pre-neoplastic lesions but was not sufficient per se to induce tumorigenesis (Lanz et al., 2003). Notably, SRA gene depleted MDA-MB-231 cells are less invasive than control cells, indicating this gene might be also critical for invasion (Foulds et al., 2010). Firstly, SRA's coactivation function is activated by two pseudouridylases, Pus1p and Pus3p, which have also been characterized as co-activators (Zhao et al., 2007). This modification alters the secondary structure and rigidity of the target SRA RNA molecules to promote proper folding, resulting in synergized co-activation function (Charette and Gray, 2000). The other positive regulators include the receptor co-activator 1 (SRC-1) (Lanz et al., 1999) and the RNA helicases P68/72 (Watanabe et al., 2001). SRC-1 belongs to p160 family co-activators (SRC1, SRC2/TIF2 and SRC3/AIB1), which can recruit other co-regulators to steroid receptors as well as promote a functional synergy between AF-1 and AF-2 domains (Louet and O'Malley, 2007; McKenna et al., 1999; Smith and O'Malley, 2004). Using co-immunoprecipitation from an expression system consisting of Xenopus oocytes programmed with in vitro generated RNA, SRA was found to associate with SRC-1 (Lanz et al., 1999). The p72/p68 proteins are DEAD-box RNA binding helicases that can physically interact with p160 family proteins and with ERα. AF-1 region (Caretti et al., 2007). The p72/p68 is able to bind to SRA through a well conserved motif in the DEAD box and synergizes with SRA and SRC2/TIF2 to co-activate ERα activity in the presence of estradiol (Caretti et al., 2006). On the other side, SRA may also serve as a platform to recruit some negative regulators consisting of the SMRT/HDAC1 associated repressor protein (SHARP) (Shi et al., 2001) and the SRA stem-loop interacting RNA binding protein (SLIRP) (Hatchell et al., 2006). SHARP was found to physically interact with corepressors through its repression domain (RD) whereas it interacts with SRA through a RNA recognition motif (RRM) (Shi et al., 2001). Similarly, SLIRP specifically binds to SRA STR-7 and attenuates SRA-mediated transactivation of endogenous ER (Hatchell et al., 2006). The emerging model of SRA action on ERα signaling had been summarized: Pus1p pseudouridylates specific SRA RNA uridine residues, leading to an optimum configuration of this RNA. The resulting active form of SRA, could stabilize complexes with p68 and SRC-1. In this case, transcription of target genes with suitable ERE will occur. In contrast, interaction with the negative regulators SLIRP and SHARP with SRA RNA may result in the inhibition of ER-mediated transcription. It has been proposed that they might act by sequestrating SRA by destabilizing the complex SRA/SRC-1 or by recruiting the nuclear receptor corepressor N-CoR at the promoter region of silenced genes (Leygue, 2007). 2.5 A broader biological role played by SRA It has been previously established that SRA action is not exclusively limited to increasing steroid receptor activity. Indeed it was also confirmed that SRA enhance the activity of other nuclear receptor (NRs), such as retinoic acid receptors, thyroid receptors Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 3. Coding SRA and SRAP 3.1 Discovery of SRAP Kawashima et al. reported in 2003 the cloning of a new rat SRA cDNA mostly identical to the core SRA sequence from exon 2 to exon 5. This cDNA was, 1188 The roles of SRA1 gene in breast cancer Yan Y, et al. unpublished results using mass spectrometry, MBD3 (methyl-CpG binding domain protein 3, a member of the nucleosome remodeling and histone deacetylase complex, Nurd), BAF 57 (a core subunit of SWI/SNF chromatin remodeling complex) and YB-1 (Y-box bindng protein, a general transcription factor) have been found to interact with SRAP (Jung et al., 2005; Chooniedass-Kothari et al., 2010). By using a similar approach, Jung et al. also found that the transcription regulators, such as, BAF 170 (BRG1 associated factor 170, also belonging to SWI/SNF chromatin remodeling complex) and YB-1 are associated with SRAP (Jung et al., 2005). It is necessary to point out that different cell line models and antibodies were used in these two groups. Jung et al. used Hela cell lines and 743 antibody (commercial available rabbit polyclonal antibody) whereas Chooniedass-Kothari used MCF7 cells stably over-expressed V5 tagged SRAP and V5 antibody. Interestingly, nobody has confirmed any proteinprotein interaction between SRAP and those potential partners by co-immunoprecipitation experiments. The observation that SRAP forms complexes with transcription factors by mass spectrometric analysis led us to investigate its direct association with transcription factors. By using recombinant SRAP and protein arrays, Chooniedass-Kothari found that SRAP interact with different transcription factors including ERα and ERβ with different binding affinities (Chooniedass-Kothari et al., 2010). To further validate the interaction between ER and SRAP, we performed GST pull down assay and a direct interaction between GST-SRAP and both full length radio-labeled estrogen receptor α and β was observed (Chooniedass-Kothari et al., 2010). Interestingly, Kawashima showed that SRAP is also able to directly interact with the AF-2 domain of AR in vitro by doing GST pull down assay (Kawashima et al., 2003). 3.3 Alternative RNA splicing of SRA gene in breast cancer The balance between co-activators and co-repressors may ultimately controls estrogen action in a given tissue (Lonard and O'Malley, 2006). A direct participation of this balance during breast tumorigenesis and cancer progression is now suspected, and a search for possible means to control it has started worldwide (Perissi and Rosenfeld, 2005; Hall and McDonnell, 2005). Alternative splicing of SRA gene might control the balance between the coding and noncoding SRA, and ultimately might function as the potential mechanism to regulate the balance between co-activators and co-repressors. however translatable in vitro encoding a putative 16 kD protein starting at the third methionine codon of the rat SRA cDNA sequence (Kawashima et al., 2003). It should be stressed that the existence of a corresponding endogenous 16 kD SRAP has never been proved. In the nucleotide database of the National Center for Biotechnology Information (NCBI), most human SRA sequences contain an intact core sequence (exon-2 to exon-5) but differ in their 5'-extremity. Interestingly, some variants having 5' end extention contain two start codons with a large open reading frame potentially encoding a 236/237 amino acid peptide. These cDNAs, as opposed to the original SRA, were translatable in vitro, as well as in vivo, leading to the production of a protein localized both in the cytoplasm and the nucleus (Emberley et al., 2003). In addition, sequence of SRAP is highly conserved among chordate and the presence of endogenous SRAP had been found in the testes, uterus, ovary and prostate, as well as mammary gland, lung and heart (Chooniedass-Kothari et al., 2004). Altogether, accumulated data has demonstrated that SRA1 gene products consist of two characteristic entities: a functional RNA, which through its core sequence, can co-activate transcription factor and a protein whose function remains yet to be fully understood. 3.2 Function of SRAP Chooniedass-Kothari et al. reported the existence of putative endogenous human SRA protein in breast cancer cells (Chooniedass-Kothari et al., 2006). A decreased response to ERα activity was observed in MCF-7 cells stably transfected with SRAP suggested that this protein might repress estrogen receptor activities (Chooniedass-Kothari et al., 2006). This result contrasts with Kawashima's results, who found that the transient transfection of full length rat SRA coding sequence and led to an activation of the response to androgen (Kurisu et al., 2006). It should be pointed out that, both coding sequence of SRA used by these two groups also contains the functional core sequence of SRA RNA proven to co-activate ERα. Therefore, it is difficult to draw any conclusions regarding the individual function of SRAP on estrogen receptor activities when functional SRA RNA and SRAP protein are co-expressed. In order to understand the functional role of SRAP independently of SRA RNA, two different groups have investigated physical protein properties by tandem mass spectrometric analysis of SRAP coimmunoprecipitation samples (Jung et al., 2005; Chooniedass-Kothari et al., 2010). Interestingly, both groups showed that SRAP is able to interact with transcriptional regulators. In Chooniedass-Kothari's Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1189 The roles of SRA1 gene in breast cancer Yan Y, et al. Figure 2: Coding and non-coding SRA transcripts in human breast cancer cells. SRA1 gene, located on chromosome 5q31.3, consists of 5 exons (boxes) and 4 introns (plain lines). The originally described SRA sequence (AF092038) contains a core sequence (light blue), necessary and sufficient for SRA RNAs to act as co-activators (Lanz et al., 1999). Three coding isoforms have now been identified (SRA1, SRA2, SRA3), which mainly differ from AF092038 by an extended 5'-extremity containing AUG initiating codons (vertical white bar in exon 1). The stop codon of the resulting open reading frame is depicted by a black vertical bar in exon5. Black stars in exon 2 and 3 correspond to a point mutation (position 98 of the core: U to C) and a point mutation followed by a full codon (position 271 of the core: G to CGAC), respectively. Three non-coding SRA isoforms containing a differentially-spliced intron-1 have been characterized: FI, full intron-1 retention; PI, partial intron-1 retention; AD, alternative 5' donor and partial intron retention. Thick straight line, 60 bp of intron 1 retained in PI; triangulated lines represent splicing events (Modified from Cooper et al. 2009). Both non-coding and coding SRA transcripts co-exist in breast cells (Figure 2, Hube et al., 2006). Using a previously validated triple-primer PCR (TP-PCR) assay (Leygue et al., 1996), which allows co-amplification and relative quantification of two transcripts sharing a common region but differing in another, we found that breast cancer cell lines co-expressed normally spliced coding SRA RNA as well as SRA RNA containing intron-1 (Hube et al., 2006). Interestingly, breast cancer cell lines differ in their relative levels of coding/noncoding SRA transcripts. In particular, the three most invasive cell lines (MDA-MB-231, 468, and BT-20) expressed the highest, whereas the "closest to normal" MCF-10A1 breast cells expressed the lowest relative levels of SRA intron-1 RNA. This suggests that a balance changed toward the production of non-coding SRA1 RNA in breast cells might be associated with growth and/or invasion properties (Hube et al., 2006). Alternative splicing events result from the relative local concentration of RNA binding proteins within the microenvironnement surrounding the nascent premRNA (Mercatante et al., 2001). We were recently able to artificially alter the balance between coding and non-coding SRA1 RNAs in T5 breast cancer cells using a previously described splicing-switching oligonucleotide strategy (Mercatante et al., 2001; Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Mercatante and Kole, 2002). This approach resulted in an increase in the production of intron retained transcripts, decrease in the expression of SRAP, resulting in an observed significant increase in the expression of the urokinase plasminogen activator (uPA, PLAU), gene intimately linked to invasion mechanisms (Harbeck et al., 2004) as well as of ERβ, involved, as highlighted earlier, in breast cancer cell growth (Han et al., 2005). 3.4 SRAP expression and relevance to breast cancer SRAP expression was assessed by Tissue Microarray (TMA) analysis of 372 breast tumors (Yan et al., 2009). SRAP levels were significantly higher in estrogen receptor-alpha positive, in progesterone receptor positive and in older patients (age > 64). When considering ER+ tumors, PR+ tumors, or young patients (≤ 64 years), patients with high SRAP expression had a significantly worse breast cancer specific survival (BCSS) than patients with low SRAP levels. SRAP also appeared as a very powerful indicator of poor prognostic for BCSS in the subset of ER+, node negative and young breast cancer patients. Altogether suggest that SRAP levels might provide additional information on potential risk of recurrence and negative outcome in a specific set of patients. 1190 The roles of SRA1 gene in breast cancer Yan Y, et al. SRA, functions as an RNA and is present in an SRC-1 complex. Cell. 1999 Apr 2;97(1):17-27 4. Conclusion Accumulated data suggest that the bi-faceted SRA/SRAP system, including SRA non-coding RNA and SRA protein, regulates estrogen receptor signaling pathways and plays a critical role in breast tumorigenesis and tumor progression. SRA is the first example of a new kind of molecules active at both RNA as well as at the protein levels. Investigating and understanding this bi-faceted system might open a new era of novel preventive or therapeutic strategies for breast cancer patients. Leygue E, Dotzlaw H, Watson PH, Murphy LC. Expression of the steroid receptor RNA activator in human breast tumors. Cancer Res. 1999 Sep 1;59(17):4190-3 McKenna NJ, Lanz RB, O'Malley BW. Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev. 1999 Jun;20(3):321-44 Charette M, Gray MW. Pseudouridine in RNA: what, where, how, and why. IUBMB Life. 2000 May;49(5):341-51 Jenuwein T, Allis CD. Translating the histone code. Science. 2001 Aug 10;293(5532):1074-80 Acknowledgements Mercatante DR, Bortner CD, Cidlowski JA, Kole R. Modification of alternative splicing of Bcl-x pre-mRNA in prostate and breast cancer cells. analysis of apoptosis and cell death. J Biol Chem. 2001 May 11;276(19):16411-7 This work is supported by the Canadian Institute of Health Research / the Canadian Breast Cancer Research Alliance (MOP-129794) and the CancerCare Manitoba Foundation (761017028). Y Yan has been supported by the MHRC (Manitoba Health Research Council) Studentship. Shi Y, Downes M, Xie W, Kao HY, Ordentlich P, Tsai CC, Hon M, Evans RM. Sharp, an inducible cofactor that integrates nuclear receptor repression and activation. Genes Dev. 2001 May 1;15(9):1140-51 Abbreviations Watanabe M, Yanagisawa J, Kitagawa H, Takeyama K, Ogawa S, Arao Y, Suzawa M, Kobayashi Y, Yano T, Yoshikawa H, Masuhiro Y, Kato S. A subfamily of RNA-binding DEAD-box proteins acts as an estrogen receptor alpha coactivator through the N-terminal activation domain (AF-1) with an RNA coactivator, SRA. EMBO J. 2001 Mar 15;20(6):1341-52 AF-1: activation function 1 AF-2: activation function 2 AR: androgen receptor DAX-1: dosage-sensitive sex reversal-adrenal hypoplasia congenital critical region on X chromosome gene 1; NR0B1 DBD: DNA binding domain ER: estrogen receptor ERE: estrogen receptor GR: glucocorticoid receptor LBD: ligand binding domain MBD3: methyl-CpG binding domain protein 3 NRs: nuclear receptors NCoR: nuclear co-repressor PLAU: urokinase plasminogen activator PR: progesterone receptor Pus1p: pseudouridine synthase 1 Pus3p: pseudouridine syntheses 3 SERM: selective estrogen receptor modulators SF-1: nuclear receptor steroidogenic factor 1 SDM: site-directed mutatagenesis SHARP: SMRT/HDAC1 associated repressor protein SLIRP: SRA stem-loop interacting RNA binding protein SRA: steroid receptor RNA activator SRAP: steroid receptor RNA activator protein SR: serine/arginine-rich proteins SRC-1: steroid receptor co-activator 1 STR: secondary structural motif YB-1: Y-box bindng protein Lanz RB, Razani B, Goldberg AD, O'Malley BW. Distinct RNA motifs are important for coactivation of steroid hormone receptors by steroid receptor RNA activator (SRA). Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16081-6 Mercatante DR, Kole R. Control of alternative splicing by antisense oligonucleotides as a potential chemotherapy: effects on gene expression. Biochim Biophys Acta. 2002 Jul 18;1587(2-3):126-32 Murphy LC, Leygue E, Niu Y, Snell L, Ho SM, Watson PH. Relationship of coregulator and oestrogen receptor isoform expression to de novo tamoxifen resistance in human breast cancer. Br J Cancer. 2002 Dec 2;87(12):1411-6 Deblois G, Giguère V. Ligand-independent coactivation of ERalpha AF-1 by steroid receptor RNA activator (SRA) via MAPK activation. J Steroid Biochem Mol Biol. 2003 Jun;85(25):123-31 Emberley E, Huang GJ, Hamedani MK, Czosnek A, Ali D, Grolla A, Lu B, Watson PH, Murphy LC, Leygue E. Identification of new human coding steroid receptor RNA activator isoforms. 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Mol Endocrinol. 2010 May;24(5):1090-105 Hatchell EC, Colley SM, Beveridge DJ, Epis MR, Stuart LM, Giles KM, Redfern AD, Miles LE, Barker A, MacDonald LM, Arthur PG, Lui JC, Golding JL, McCulloch RK, Metcalf CB, Wilce JA, Wilce MC, Lanz RB, O'Malley BW, Leedman PJ. SLIRP, a small SRA binding protein, is a nuclear receptor corepressor. Mol Cell. 2006 Jun 9;22(5):657-68 This article should be referenced as such: Yan Y, Cooper C, Leygue E. The roles of SRA1 gene in breast cancer. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):1186-1192. Hube F, Guo J, Chooniedass-Kothari S, Cooper C, Hamedani MK, Dibrov AA, Blanchard AA, Wang X, Deng G, Myal Y, Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1192 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Instructions to Authors Manuscripts submitted to the Atlas must be submitted solely to the Atlas. Iconography is most welcome: there is no space restriction. 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See also: "Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication - Updated October 2004": http://www.icmje.org. http://AtlasGeneticsOncology.org © ATLAS - ISSN 1768-3262 The roles of SRA1 gene in breast cancer Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Yan Y, et al. 1194