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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Volume 16 - Number 1 January 2012 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 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, Marie-Christine Jacquemot-Perbal, Maureen Labarussias, Vanessa Le Berre, Anne Malo, Catherine Morel-Pair, Laurent Rassinoux, 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. 2012; 16(1) 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 16, Number 1, January 2012 Table of contents Gene Section ADAM10 (ADAM metallopeptidase domain 10) Pascal Gelebart, Hanan Armanious, Raymond Lai 1 BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast)) Victor M Bolanos-Garcia, Tom L Blundell 7 FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed) Mark Pickard 12 GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor)) Stephanie Schulz, Scott A Waldman 18 LIN28B (lin-28 homolog B (C. elegans)) Yung-Ming Jeng 20 PKD1 (polycystic kidney disease 1 (autosomal dominant)) Ying-Cai Tan, Hanna Rennert 22 AMFR (autocrine motility factor receptor) Yalcin Erzurumlu, Petek Ballar 25 ASH2L (ash2 (absent, small, or homeotic)-like (Drosophila)) Paul F South, Scott D Briggs 30 CD109 (CD109 molecule) Shinji Mii, Yoshiki Murakumo, Masahide Takahashi 34 CLDN7 (claudin 7) Ana Carolina de Carvalho, Andre Vettore 37 CSE1L (CSE1 chromosome segregation 1-like (yeast)) Ming-Chung Jiang 41 DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5) Zhi-Ren Liu 44 Leukaemia Section t(13;19)(q14;p13) Jean-Loup Huret 48 t(17;17)(q21;q24), del(17)(q21q24) Jean-Loup Huret 49 Deep Insight Section MicroRNAs and Cancer Federica Calore, Muller Fabbri Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 51 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 Case Report Section Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis Francesca Cambosu, Giuseppina Fogu, Paola Maria Campus, Claudio Fozza, Luigi Podda, Andrea Montella, Maurizio Longinotti 70 Educational Items Section Weird animal genomes and sex chromosome evolution Jenny Graves Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 73 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review ADAM10 (ADAM metallopeptidase domain 10) Pascal Gelebart, Hanan Armanious, Raymond Lai Department of Laboratory Medicine and Pathology, University of Alberta, Room 1466, 11560 University Avenue, T6G 1Z2-Edmonton, Alberta, Canada (PG, HA, RL) Published in Atlas Database: July 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/ADAM10ID44397ch15q21.html DOI: 10.4267/2042/47258 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity part is divided into 16 exons. Other names: AD10, CD156c, HsT18717, MADM, kuz HGNC (Hugo): ADAM10 Location: 15q21.3 Only one type of transcript has been described. The 2247-nucleotide transcript encodes a protein of 748 amino acid residues. The first and last exons are partially untranslated. Transcription Pseudogene DNA/RNA None described so far. Description The gene spans a region of 15.36 kb and the coding Figure 1. Representation of the ADAM10 gene organization. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 1 ADAM10 (ADAM metallopeptidase domain 10) Gelebart P, et al. Two proteins, the convertase 7 and the furin, have been implicated in the activation of ADAM10 (Anders et al., 2001). To date the major function of ADAM10 appears to be attributed to its enzymatic activity as a metalloproteinase. In fact, ADAM10 is involved in the intra-membrane proteolysis process, whereby it mediates ectodomain shedding of various membrane bound receptors, adhesion molecules, growth factors and cytokines like TNF-alpha (Rosendahl et al., 1997; Lunn et al., 1997; Hikita et al., 2009; Mezyk-Kopec et al., 2009), Notch (Hartmann et al., 2002; Gibb et al., 2010), E-cadherin (Maretzky et al., 2005), Ephrin (Janes et al., 2005), HER-2 (Liu et al., 2006), CD30 (Eichenauer et al., 2007), CD44 (Anderegg et al., 2009) and IL-6 receptor to name a few. The functional role of the SH3 domains of ADAM10 has never been studied. Moreover, the recent observation that ADAM10 can be found in the nucleus of some cells raises the possibility of new and uncovers function of ADAM10 (Arima et al., 2007). ADAM10 seems to be detrimental for embryogenesis as the knockout mice for ADAM10 die at day 9.5 of embryogenesis (Hartmann et al., 2002). The mice present several developmental defects in the nervous central system as well in the cardiovascular system. This latest observation correlates well with the fact that ADAM10 transcript is highly expressed in cardiomyocyte. In human, ADAM10 was recently been demonstrated to be a regulator of the lymphocyte development (Gibb et al., 2011). Protein Description ADAM10 is a metalloproteinase composed of 748 residues. Expression ADAM10 RNA has been reported to be present in wide range of human tissue (Yanai et al., 2005). Data obtained from GeneAtlas have shown that ADAM10 transcript is the most highly expressed in myeloid, NK cells and monocytes as well as cardiomyocytes and smooth muscle cells (figure 3). At the protein level, ADAM10 has been reported in epithelials tissue of the heart, liver and kidney (Hall and Erickson, 2003). Localisation ADAM10 is localized at the plasma membrane. However, nuclear localization of ADAM10 has been reported in prostate cancer and in mantle cell lymphoma cells (Armanious et al., 2011). Function ADAM10 belongs to the family of metalloproteinases (Chantry et al., 1989; Chantry and Glynn, 1990; Edwards et al., 2008). ADAM10 protein is composed of multiple functional domains that include: a prodomain, a catalytic domain, a cysteine-rich domain, a transmembraneous domain, a cytoplasmic domain and a SH3 domain (Seals and Courtneidge, 2003; Edwards et al., 2008) (see figure 4). ADAM10 is synthesized as a pro-protein and therefore needs to be cleaved to be activated (Anders et al., 2001). Figure 2. Crystal structure of ADAM10 Disintegrin and cysteine-rich domain at 2.9 A resolution. Adapted from PDB (access number: 2AO7). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 2 ADAM10 (ADAM metallopeptidase domain 10) Gelebart P, et al. Figure 3. ADAM10 tissue expression profile. Adapted from GeneAtlas U113A. Figure 4. ADAM10 protein structure organization. Brain tumors Mutations Note ADAM10 protein has been reported to be highly expressed in the human central nervous system (Kärkkäinen et al., 2000). Recently, two different studies (Kohutek et al., 2009; Formolo et al., 2011) have uncovered the function of ADAM10 in the cell migration and invasiveness process of glioblastoma cells. In fact the authors have shown that ADAM10 by mediating the cleavage of N-cadherin was found to regulate the migratory properties of glioblastoma cells (Kohutek et al., 2009). On the other hand, the protein expression of ADAM10 was found to be higher in cell with strong invasiveness capability. Note No mutation has been reported so far. Implicated in Various cancers Note ADAM family members have been recently involved in malignant progression and development (Mochizuki and Okada, 2007; Rocks et al., 2008; Wagstaff et al., 2011; Duffy et al., 2009). ADAM10 has been shown to be constitutively active in a number of solid tumors, and this biochemical defect is implicated in the pathogenesis of many tumors. The following paragraphs will summarize what has been discovered about the function of ADAM10 in cancer. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Prostate cancer Note Prostate cancer is one of the most frequent cancers in men. The cause of prostate cancer development is 3 ADAM10 (ADAM metallopeptidase domain 10) Gelebart P, et al. unknown but is likely to be arising from several factors. Development of prostate cancer is androgen-dependent in early stages of the disease but cell growth became androgen-independent. ADAM10 have been found to be expressed in all prostate tumor samples (Karan et al., 2003). Interestingly, McCulloch et al. have observed that ADAM10 expression was up-regulated by androgen stimulation. Those observations were confirmed in a study published by Arima et al. However, in this work they reveal that ADAM10 was predominantly localized in the nucleus of cancer cells and show that ADAM10 can co-immunoprecipitate with androgen receptor in the nucleus. Moreover, they also observed that nuclear expression of ADAM10 was correlating with several biological parameters like the Gleason score and prostate specific antigen expression. Inhibition of ADAM10 expression by a siRNA approach was able to induce a cell proliferation decrease of prostate cancer cells. This study suggests for the first time that ADAM10 may have some function in the nucleus by regulating androgen receptor function. outcome (Wang et al., 2011). Using immunohistochemistry, it was also found that ADAM10 is over-expressed in squamous cell carcinomas of the oral cavity, as compared to the benign epithelial cells; knockdown of ADAM10 expression using siRNA in the cell lines derived from those tumors induces a significant decrease in cell growth (Ko et al., 2007). Melanoma, pancreatic cancer and adenoid cystic carcinoma Note The expression of ADAM10 has been investigated in melanoma and Lee et al. have reported that ADAM10 is over-expressed in melanoma metastasis in comparison to primary melanoma cells. Similar findings were made in pancreatic cancer, where inhibition of ADAM10 expression in pancreatic carcinoma cell lines also resulted in a significant decrease in invasiveness and migration (Gaida et al., 2010). Hematologic malignancies Breast cancer Note Recently, Armanious et al. have described for the first time the function of ADAM10 in non solid tumors. They have reported that ADAM10 is constitutively activated and over-expressed in different form of B-cell lymphoma like mantle cell lymphoma and diffuse large B-cell lymphoma. Moreover, the authors have described that inhibition of ADAM10 leads to a decrease of cell proliferation. On the other hand, stimulation of mantle cells with the recombinant active form of ADAM10 increases further their proliferation. Additionally, they also demonstrated, as reported previously in the literature, that ADAM10 was responsible for the release of active from of TNF-alpha that in turn was contributing to the activation of the NF-kappab pathways. Note Expressions of different members of the ADAM family have been investigated in breast cancer. Despite that some ADAM family members present differential expression between non neoplastic and breast cancer tissue, no difference was observed for ADAM10 (Lendeckel et al., 2005). Nevertheless, Liu and coworkers have recently described than ADAM10 was the principal responsible for HER2 shedding in HER2 over-expressing breast cancer. The cleavage of HER2 liberates the extracellular domain of HER2 leaving a p95 fragment containing the transmembrane domain as well as the intracellular domain. This p95 fragment presents constitutive kinase activation and its expression correlates with a poor prognosis. The author demonstrated that in conjunction with low amount of HER2 inhibitor, ADAM10 inhibition was inducing a decrease in cell proliferation. To be noted Note To summarize, the function of ADAM protein family members emerge as an important player in the pathobiology of various form of cancers. Therefore, they represent today a new therapeutic target of choice for cancer therapy. In particular, ADAM10 is the object of intense drug development (Soundararajan et al., 2009; Crawford et al., 2009; Yavari et al., 1998; Moss et al., 2008). Colon and gastric and oral carcinomas Note Deregulation of ADAM10 in colon cancer development has been reported in several studies. Knösel et al. have reported that ADAM10 expression in colorectal cancer patient samples, detectable by immunohistochemistry was found to correlate with higher clinical stage. Moreover, it has been demonstrated that xenografting of colorectal cancer cells with enforced expression of ADAM10 in nude mice induced formation of liver metastasis compared to the negative control cells, and this effect can be attributed to ADAM10-mediated cleavage and release of L1-CAM, a cell adhesion molecule (Gavert et al., 2007). Similarly to Knösel et al., ADAM10 expression was associated with gastric cancer progression and correlates with worst prognostic Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) References Chantry A, Gregson NA, Glynn P. A novel metalloproteinase associated with brain myelin membranes. Isolation and characterization. J Biol Chem. 1989 Dec 25;264(36):21603-7 Chantry A, Glynn P. A novel metalloproteinase originally isolated from brain myelin membranes is present in many tissues. Biochem J. 1990 May 15;268(1):245-8 4 ADAM10 (ADAM metallopeptidase domain 10) Gelebart P, et al. Lunn CA, Fan X, Dalie B, Miller K, Zavodny PJ, Narula SK, Lundell D. Purification of ADAM 10 from bovine spleen as a TNFalpha convertase. FEBS Lett. 1997 Jan 6;400(3):333-5 Lancet D, Shmueli O. Genome-wide midrange transcription profiles reveal expression level relationships in human tissue specification. Bioinformatics. 2005 Mar 1;21(5):650-9 Rosendahl MS, Ko SC, Long DL, Brewer MT, Rosenzweig B, Hedl E, Anderson L, Pyle SM, Moreland J, Meyers MA, Kohno T, Lyons D, Lichenstein HS. Identification and characterization of a pro-tumor necrosis factor-alpha-processing enzyme from the ADAM family of zinc metalloproteases. J Biol Chem. 1997 Sep 26;272(39):24588-93 Liu PC, Liu X, Li Y, Covington M, Wynn R, Huber R, Hillman M, Yang G, Ellis D, Marando C, Katiyar K, Bradley J, Abremski K, Stow M, Rupar M, Zhuo J, Li YL, Lin Q, Burns D, Xu M, Zhang C, Qian DQ, He C, Sharief V, Weng L, Agrios C, Shi E, Metcalf B, Newton R, Friedman S, Yao W, Scherle P, Hollis G, Burn TC. Identification of ADAM10 as a major source of HER2 ectodomain sheddase activity in HER2 overexpressing breast cancer cells. Cancer Biol Ther. 2006 Jun;5(6):657-64 Yavari R, Adida C, Bray-Ward P, Brines M, Xu T. Human metalloprotease-disintegrin Kuzbanian regulates sympathoadrenal cell fate in development and neoplasia. Hum Mol Genet. 1998 Jul;7(7):1161-7 Arima T, Enokida H, Kubo H, Kagara I, Matsuda R, Toki K, Nishimura H, Chiyomaru T, Tatarano S, Idesako T, Nishiyama K, Nakagawa M. Nuclear translocation of ADAM-10 contributes to the pathogenesis and progression of human prostate cancer. Cancer Sci. 2007 Nov;98(11):1720-6 Kärkkäinen I, Rybnikova E, Pelto-Huikko M, Huovila AP. Metalloprotease-disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS. Mol Cell Neurosci. 2000 Jun;15(6):547-60 Eichenauer DA, Simhadri VL, von Strandmann EP, Ludwig A, Matthews V, Reiners KS, von Tresckow B, Saftig P, Rose-John S, Engert A, Hansen HP. ADAM10 inhibition of human CD30 shedding increases specificity of targeted immunotherapy in vitro. Cancer Res. 2007 Jan 1;67(1):332-8 Anders A, Gilbert S, Garten W, Postina R, Fahrenholz F. Regulation of the alpha-secretase ADAM10 by its prodomain and proprotein convertases. FASEB J. 2001 Aug;15(10):18379 Gavert N, Sheffer M, Raveh S, Spaderna S, Shtutman M, Brabletz T, Barany F, Paty P, Notterman D, Domany E, BenZe'ev A. Expression of L1-CAM and ADAM10 in human colon cancer cells induces metastasis. Cancer Res. 2007 Aug 15;67(16):7703-12 Hartmann D, de Strooper B, Serneels L, Craessaerts K, Herreman A, Annaert W, Umans L, Lübke T, Lena Illert A, von Figura K, Saftig P. The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. Hum Mol Genet. 2002 Oct 1;11(21):261524 Ko SY, Lin SC, Wong YK, Liu CJ, Chang KW, Liu TY. Increase of disintergin metalloprotease 10 (ADAM10) expression in oral squamous cell carcinoma. Cancer Lett. 2007 Jan 8;245(12):33-43 Hall RJ, Erickson CA. ADAM 10: an active metalloprotease expressed during avian epithelial morphogenesis. Dev Biol. 2003 Apr 1;256(1):146-59 Kopitz C, Gerg M, Bandapalli OR, Ister D, Pennington CJ, Hauser S, Flechsig C, Krell HW, Antolovic D, Brew K, Nagase H, Stangl M, von Weyhern CW, Brücher BL, Brand K, Coussens LM, Edwards DR, Krüger A. Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by induction of hepatocyte growth factor signaling. Cancer Res. 2007 Sep 15;67(18):8615-23 Karan D, Lin FC, Bryan M, Ringel J, Moniaux N, Lin MF, Batra SK. Expression of ADAMs (a disintegrin and metalloproteases) and TIMP-3 (tissue inhibitor of metalloproteinase-3) in human prostatic adenocarcinomas. Int J Oncol. 2003 Nov;23(5):136571 Seals DF, Courtneidge SA. The ADAMs family of metalloproteases: multidomain proteins with multiple functions. Genes Dev. 2003 Jan 1;17(1):7-30 Mochizuki S, Okada Y. ADAMs in cancer cell proliferation and progression. Cancer Sci. 2007 May;98(5):621-8 McCulloch DR, Akl P, Samaratunga H, Herington AC, Odorico DM. Expression of the disintegrin metalloprotease, ADAM-10, in prostate cancer and its regulation by dihydrotestosterone, insulin-like growth factor I, and epidermal growth factor in the prostate cancer cell model LNCaP. Clin Cancer Res. 2004 Jan 1;10(1 Pt 1):314-23 Edwards DR, Handsley MM, Pennington CJ. The ADAM metalloproteinases. Mol Aspects Med. 2008 Oct;29(5):258-89 Janes PW, Saha N, Barton WA, Kolev MV, Wimmer-Kleikamp SH, Nievergall E, Blobel CP, Himanen JP, Lackmann M, Nikolov DB. Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans. Cell. 2005 Oct 21;123(2):291-304 Rocks N, Paulissen G, El Hour M, Quesada F, Crahay C, Gueders M, Foidart JM, Noel A, Cataldo D. Emerging roles of ADAM and ADAMTS metalloproteinases in cancer. Biochimie. 2008 Feb;90(2):369-79 Moss ML, Stoeck A, Yan W, Dempsey PJ. ADAM10 as a target for anti-cancer therapy. Curr Pharm Biotechnol. 2008 Feb;9(1):2-8 Anderegg U, Eichenberg T, Parthaune T, Haiduk C, Saalbach A, Milkova L, Ludwig A, Grosche J, Averbeck M, Gebhardt C, Voelcker V, Sleeman JP, Simon JC. ADAM10 is the constitutive functional sheddase of CD44 in human melanoma cells. J Invest Dermatol. 2009 Jun;129(6):1471-82 Knösel T, Emde A, Schlüns K, Chen Y, Jürchott K, Krause M, Dietel M, Petersen I. Immunoprofiles of 11 biomarkers using tissue microarrays identify prognostic subgroups in colorectal cancer. Neoplasia. 2005 Aug;7(8):741-7 Lendeckel U, Kohl J, Arndt M, Carl-McGrath S, Donat H, Röcken C. Increased expression of ADAM family members in human breast cancer and breast cancer cell lines. J Cancer Res Clin Oncol. 2005 Jan;131(1):41-8 Crawford HC, Dempsey PJ, Brown G, Adam L, Moss ML. ADAM10 as a therapeutic target for cancer and inflammation. Curr Pharm Des. 2009;15(20):2288-99 Duffy MJ, McKiernan E, O'Donovan N, McGowan PM. The role of ADAMs in disease pathophysiology. Clin Chim Acta. 2009 May;403(1-2):31-6 Maretzky T, Reiss K, Ludwig A, Buchholz J, Scholz F, Proksch E, de Strooper B, Hartmann D, Saftig P. ADAM10 mediates Ecadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation. Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9182-7 Hikita A, Tanaka N, Yamane S, Ikeda Y, Furukawa H, Tohma S, Suzuki R, Tanaka S, Mitomi H, Fukui N. Involvement of a disintegrin and metalloproteinase 10 and 17 in shedding of tumor necrosis factor-alpha. Biochem Cell Biol. 2009 Aug;87(4):581-93 Yanai I, Benjamin H, Shmoish M, Chalifa-Caspi V, Shklar M, Ophir R, Bar-Even A, Horn-Saban S, Safran M, Domany E, Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 5 ADAM10 (ADAM metallopeptidase domain 10) Gelebart P, et al. Kohutek ZA, diPierro CG, Redpath GT, Hussaini IM. ADAM10-mediated N-cadherin cleavage is protein kinase C-alpha dependent and promotes glioblastoma cell migration. J Neurosci. 2009 Apr 8;29(14):4605-15 upregulated in melanoma metastasis compared with primary melanoma. J Invest Dermatol. 2010 Mar;130(3):763-73 Xu Q, Liu X, Chen W, Zhang Z. Inhibiting adenoid cystic carcinoma cells growth and metastasis by blocking the expression of ADAM 10 using RNA interference. J Transl Med. 2010 Dec 20;8:136 Mezyk-Kopeć R, Bzowska M, Stalińska K, Chełmicki T, Podkalicki M, Jucha J, Kowalczyk K, Mak P, Bereta J. Identification of ADAM10 as a major TNF sheddase in ADAM17-deficient fibroblasts. Cytokine. 2009 Jun;46(3):30915 Armanious H, Gelebart P, Anand M, Belch A, Lai R. Constitutive activation of metalloproteinase ADAM10 in mantle cell lymphoma promotes cell growth and activates the TNFα/NFκB pathway. Blood. 2011 Jun 9;117(23):6237-46 Soundararajan R, Sayat R, Robertson GS, Marignani PA. Triptolide: An inhibitor of a disintegrin and metalloproteinase 10 (ADAM10) in cancer cells. Cancer Biol Ther. 2009 Nov;8(21):2054-62 Formolo CA, Williams R, Gordish-Dressman H, MacDonald TJ, Lee NH, Hathout Y. Secretome signature of invasive glioblastoma multiforme. J Proteome Res. 2011 Jul 1;10(7):3149-59 Gaida MM, Haag N, Günther F, Tschaharganeh DF, Schirmacher P, Friess H, Giese NA, Schmidt J, Wente MN. Expression of A disintegrin and metalloprotease 10 in pancreatic carcinoma. Int J Mol Med. 2010 Aug;26(2):281-8 Gibb DR, Saleem SJ, Chaimowitz NS, Mathews J, Conrad DH. The emergence of ADAM10 as a regulator of lymphocyte development and autoimmunity. Mol Immunol. 2011 Jun;48(11):1319-27 Gibb DR, El Shikh M, Kang DJ, Rowe WJ, El Sayed R, Cichy J, Yagita H, Tew JG, Dempsey PJ, Crawford HC, Conrad DH. ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo. J Exp Med. 2010 Mar 15;207(3):623-35 Wagstaff L, Kelwick R, Decock J, Edwards DR. The roles of ADAMTS metalloproteinases in tumorigenesis and metastasis. Front Biosci. 2011 Jan 1;16:1861-72 Wang YY, Ye ZY, Li L, Zhao ZS, Shao QS, Tao HQ. ADAM 10 is associated with gastric cancer progression and prognosis of patients. J Surg Oncol. 2011 Feb;103(2):116-23 Gutwein P, Schramme A, Abdel-Bakky MS, Doberstein K, Hauser IA, Ludwig A, Altevogt P, Gauer S, Hillmann A, Weide T, Jespersen C, Eberhardt W, Pfeilschifter J. ADAM10 is expressed in human podocytes and found in urinary vesicles of patients with glomerular kidney diseases. J Biomed Sci. 2010 Jan 13;17:3 This article should be referenced as such: Gelebart P, Armanious H, Lai R. ADAM10 (ADAM metallopeptidase domain 10). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):1-6. Lee SB, Schramme A, Doberstein K, Dummer R, Abdel-Bakky MS, Keller S, Altevogt P, Oh ST, Reichrath J, Oxmann D, Pfeilschifter J, Mihic-Probst D, Gutwein P. ADAM10 is Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 6 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast)) Victor M Bolanos-Garcia, Tom L Blundell Department of Biochemistry, University of Cambridge, CB2 1GA, Cambridge, UK (VMBG, TLB) Published in Atlas Database: July 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/BUB1ID853ch2q13.html DOI: 10.4267/2042/47259 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Amino acid sequence (FASTA format). Identity Description Other names: BUB1A, BUB1L, hBUB1 HGNC (Hugo): BUB1 Location: 2q13 Note The multidomain protein kinase BUB1 is a central component of the mitotic checkpoint for spindle assembly (SAC). This evolutionary conserved and essential self-monitoring system of the eukaryotic cell cycle ensures the high fidelity of chromosome segregation by delaying the onset of anaphase until all chromosomes are properly bi-oriented on the microtubule spindle. 1085 amino acids, 122.37 kDa. Expression Ubiquituously expressed. Localisation Cytoplasmic in interphase cells. It is localized in nuclear kinetochores in cells with an unsatisfied mitotic checkpoint in a process that requires BUB1 binding to Blinkin and BUB3. Function BUB1 is required for chromosome congression, kinetochore localization of BUBR1, CENP-E, CENP-F and Mad2 in cells with mitotic checkpoint unsatisfied and for the establishment and/or maintenance of efficient bipolar attachment to spindle microtubules (Johnson et al., 2004; Lampson and Kapoor, 2005; McGuinness et al., 2009). Deletion of Bub1 from S. pombe increases the rate of chromosome missegregation (Bernard et al., 1998) while deletion of Bub1 from S. cerevisiae results in slow growth and elevated chromosome loss (Warren et al., 2002). BUB1 is recruited very early in prophase (Wong and Fang, 2006) and is essential for assembly of the functional inner centromere (Taylor et al., 1998; Boyarchuk et al., 2007). DNA/RNA Description The gene spans 40.2 kb and is composed of 25 exons. Transcription NM_004336.3 Protein Note Uniprot accession number: NP_004327.1. ENZYME entry (serine/threonine protein kinase): EC 2.7.11.1. Figure 1. Schematic representation of the human bub1 gene demonstrating the relative size of each of the 25 exons (introns are not drawn to scale). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 7 BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast)) Bolanos-Garcia VM, Blundell TL Figure 2. Domain organization of BUB1. Three main regions can be identified in the BUB1 gene product: a conserved N-terminal region, which contains the kinetochore localization domain; an intermediate, non-conserved region, which is required for Bub3 binding; and a Cterminal region containing a catalytic serine/threonine kinase domain. The main functions associated with the different BUB1 regions are also indicated. It accumulates at the kinetochore in SAC-activated cells and assures the correct kinetochore formation. The N-terminal region mediates the binding of BUB1 to the mitotic kinetochore protein Blinkin (a protein also commonly referred to as KNL1/Spc105/AF15q14); the interaction is essential for the kinetochore localization of BUB1 induced in cells with an unsatisfied mitotic checkpoint (Kiyomitsu et al., 2007). N-terminal BUB1 is organised as a triple tandem of the TPR motif (Bolanos-Garcia et al., 2009). In fission yeast, the Bub1 N-terminal residues 1-179 are required for targeting the protein Shugoshin 1 (SGO1) to centromeres (Vaur et al., 2005) while deletion of residues 28-160 results in a truncated protein unable to recruit Bub3 and Mad3/BUB1B to kinetochores (Vanoosthuyse et al., 2004). The Cterminal region contains a catalytic, serine threonine kinase domain that resembles the mechanism of activation of CDKs by cyclins (Kang et al., 2008). mouse, rat, chicken, and zebrafish. Homology exists with the gene encoding for the mitotic checkpoint kinase BUBR1 (a BUB1 paralogue) (Bolanos-Garcia and Blundell, 2011). Mutations The following somatic mutations have been reported to date: A130->S (Shichiri et al., 2002); deletion delta76141 (Cahill et al., 1998); 140, transition of the splicing donor site (Cahill et al., 1998); S492->Y (Cahill et al., 1998); deletion delta827 (Ouyang et al., 2002); G250>N (Ohshima et al., 2000); S950->G (Imai et al., 1999); Y259->C (Hempen et al., 2003); H265->N (Hempen et al., 2003). It could not be determined whether the R209->Q substitution was the result of a somatic mutation or due to a rare polymorphism because constitutional DNA from the patient harbouring this mutation was not available (Sato et al., 2000). The clinical condition associated to each mutation is described in Table 1. The mapping of residues substitutions onto the BUB1 domains is depicted in Figure 3. Homology The bub1 gene is conserved in chimpanzee, cow, Bub1 region Mutation Residue Domain GAG→GAT E36→D N-terminal Colorectal cancer Cahill et al., 1999 ∆76-141, frameshift Colorectal cancer Cahill et al., 1998 GCT→TCT A130→S Lymph node metastasis Shichiri et al., 2002 G→A 140, transition of the splicing donor site Colorectal cancer Cahill et al., 1998 Lung cancer Sato et al., 2000 ATLL Ohshima et al., 2000* GGT→GAT G250→N TAT→TGT Y259→C Pancreatic cancer Hempen et al., 2003 CAC→AAC H265→N Pancreatic cancer Hempen et al., 2003 S375→F Colorectal cancer Saeki et al., 2002 S492→Y Colorectal cancer Cahill et al., 1998 K566→R Colorectal cancer Saeki et al., 2002 P648→R Colorectal cancer Cahill et al., 1999 ∆827, frameshift Tyroid follicular adenoma Ouyang et al., 2002 Colorectal cancer Imai et al., 1999 TCC→TTC Middle region of low TCT→TAT structural AAG→AGG complexity CCC→CGC Deletion C-terminal Reference Deletion CGA→CAA R209→Q GLEBS motif Clinical condition S950→G TPR domain Kinase domain Table 1. Human bub1 mutations associated with cancer. *These authors incorrectly number these residues; the numbering shown here is the correct. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 8 BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast)) Bolanos-Garcia VM, Blundell TL Figure 3. Mapping of cancer associated substitutions onto the amino acid sequence of human BUB1. phenylalanine (TTC) at codon 375 while the other has a lysine (AAG) substituted for arginine (AGG) at codon 566 (Saeki et al., 2002). S375F showed a welldifferentiated HCC in cirrhotic liver caused by hepatitis B virus, whereas K566R showed a moderately differentiated HCC in hepatitis C virus induced cirrhotic liver. Genomic DNA extracted from nontumorous liver tissue revealed the same variants in both cases. Implicated in Colorectal cancer Disease Colorectal cancer, also referred to as bowel cancer, is characterized by neoplasia in the colon, rectum, or vermiform appendix. Colorectal cancer is the third most commonly diagnosed cancer in the world and fourth most frequent cause of cancer death in males. More than half of the people who die of colorectal cancer live in a developed region of the world. Cytogenetics RT-PCR mediated amplification and direct sequencing of the entire BUB1 coding region in the colorectal cancer cell line V400 revealed an internal deletion of 197 bp of this gene (Cahill et al., 1998). The deletion results in the remotion of codons 76 to 141 and creates a frameshift immediately thereafter. Sequence analysis of cDNA from another colorectal cancer cell line, V429, revealed a missense mutation at codon 492 that resulted in the substitution of tyrosine for a conserved serine (Cahill et al., 1998). The V400 and V429 mutations were heterozygous, somatic and present in primary tumours but not in normal tissues. Another heterozygous BUB1 missense mutation (AGT to GGT) at codon 950 has been identified (Imai et al., 1999). Lung cancer Disease Lung cancer is the most frequently diagnosed cancer among men. The mortality rate is the highest among men and the second highest among women worldwide. The main types of lung cancer are small-cell lung carcinoma and non-small-cell lung carcinoma. Nonsmall-cell lung carcinoma is sometimes treated with surgery, while small-cell lung carcinoma usually responds better to chemotherapy and radiation. Lung cancer cells harbour many cytogenetic abnormalities suggestive of allele loss, including non-reciprocal translocations and aneuploidy. The stage of the disease is a strong predictor of survival, suggesting that early detection is needed for improvement in treatment outcomes. Cytogenetics A nucleotide change of the BUB1 gene that results in the substitution of Arginine by Glutamine R209Q has been identified in the cell line NCI-H345 (Sato et al., 2000). Unfortunately, it was not possible to determine whether the change was a somatic mutation or a rare polymorphism because constitutional DNA from this patient was not available. Hepatocellular carcinoma (HCC) Disease Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide and it accounts for most liver cancers. HCC occurs more often in men than women and is more common in people ages 30-50. Hepatitis virus infection, alcohol consumption, and dietary exposure to toxins such as aflatoxin B1 are associated with the occurrence of HCC. Cytogenetics Two BUB1 gene variants have been identified in HCC specimens (Saeki et al., 2002). The expression product of one variant has a serine (TCC) substituted for Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Adult T-cell leukaemia/lymphoma (ATLL) Disease Lymphomas, malignancies of the lymphoid cells, are divided on the basis of their pathologic features into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma 9 BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast)) (NHL). Adult T-cell leukemia/lymphoma (ATLL) is usually a highly aggressive non-Hodgkin's lymphoma of the patient's own T-cells with no characteristic histologic appearance except for a diffuse pattern and a mature T-cell phenotype. The frequent isolation of HTLV-1 from patients with this disease and the detection of HTLV-1 proviral genome in ATLL leukemic cells suggest that HTLV-1 causes ATLL. Cytogenetics A BUB1 missense mutation of G to A at codon 250 (GGT to GAT) has been reported (Ohshima et al., 2000). Lymph node metastasis Disease Certain cancers spread in a predictable fashion from where the cancer started. Because the flow of lymph is directional, if the cancer spreads it will spread first to lymph nodes close to the tumor before it spreads to other parts of the body. Cytogenetics A BUB1 missense somatic mutation (nucleotide 437 GCT to TCT transition) that replaces Ala to Ser at codon 130 has been identified in an ascending colorectal carcinoma (Shichiri et al., 2002). Pancreatic cancer References Disease The term pancreatic cancer usually refers to adenocarcinoma that arises within the exocrine component of the pancreas. Pancreatic cancer is one of the most aggressive diseases with most cancers and often has a poor prognosis: for all stages combined, the 1- and 5-year relative survival rates are 25% and 6%, respectively; for local disease the 5-year survival is approximately 20% while the median survival for locally advanced and for metastatic disease, which collectively represent over 80% of individuals, is about 10 and 6 months respectively. Cytogenetics Two missense variants in the BUB1 gene have been identified in the aneuploid pancreatic cell line Hs766T (Hempen et al., 2003). These mutations are found in the same allele, accompanied by a wild-type BUB1 allele. Mutation of nucleotide 776 from an adenine to a guanine results in an amino acid change at codon 259 from tyrosine to cysteine (Y259C). A second mutation at nucleotide 793 changed a cytosine to an adenine (C to A) thus resulting in the mutant H265N (Hempen et al., 2003). Taylor SS, McKeon F. Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage. Cell. 1997 May 30;89(5):727-35 Bernard P, Hardwick K, Javerzat JP. Fission yeast bub1 is a mitotic centromere protein essential for the spindle checkpoint and the preservation of correct ploidy through mitosis. J Cell Biol. 1998 Dec 28;143(7):1775-87 Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B. Mutations of mitotic checkpoint genes in human cancers. Nature. 1998 Mar 19;392(6673):300-3 Cahill DP, da Costa LT, Carson-Walter EB, Kinzler KW, Vogelstein B, Lengauer C. Characterization of MAD2B and other mitotic spindle checkpoint genes. Genomics. 1999 Jun 1;58(2):181-7 Imai Y, Shiratori Y, Kato N, Inoue T, Omata M. Mutational inactivation of mitotic checkpoint genes, hsMAD2 and hBUB1, is rare in sporadic digestive tract cancers. Jpn J Cancer Res. 1999 Aug;90(8):837-40 Ohshima K, Haraoka S, Yoshioka S, Hamasaki M, Fujiki T, Suzumiya J, Kawasaki C, Kanda M, Kikuchi M. Mutation analysis of mitotic checkpoint genes (hBUB1 and hBUBR1) and microsatellite instability in adult T-cell leukemia/lymphoma. Cancer Lett. 2000 Oct 1;158(2):141-50 Thyroid follicular adenoma Sato M, Sekido Y, Horio Y, Takahashi M, Saito H, Minna JD, Shimokata K, Hasegawa Y. Infrequent mutation of the hBUB1 and hBUBR1 genes in human lung cancer. Jpn J Cancer Res. 2000 May;91(5):504-9 Disease Almost all thyroid adenomas are follicular adenomas. Follicular adenomas can be described as "cold", "warm" or "hot" depending on their level of function. Histopathologically, follicular adenomas can be classified according to their cellular architecture and relative amounts of cellularity and colloid into the following types: - fetal (microfollicular), which have the potential for microinvasion, - colloid (macrofollicular), which do not have any potential for microinvasion, - embryonal (atypical), which have the potential for microinvasion. Cytogenetics A thyroid follicular carcinoma that has a 2-bp somatic deletion (G2480/A2481) of BUB1 has been reported by Ouyang and collaborators (2002). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Bolanos-Garcia VM, Blundell TL Ouyang B, Knauf JA, Ain K, Nacev B, Fagin JA. Mechanisms of aneuploidy in thyroid cancer cell lines and tissues: evidence for mitotic checkpoint dysfunction without mutations in BUB1 and BUBR1. Clin Endocrinol (Oxf). 2002 Mar;56(3):341-50 Saeki A, Tamura S, Ito N, Kiso S, Matsuda Y, Yabuuchi I, Kawata S, Matsuzawa Y. Frequent impairment of the spindle assembly checkpoint in hepatocellular carcinoma. Cancer. 2002 Apr 1;94(7):2047-54 Shichiri M, Yoshinaga K, Hisatomi H, Sugihara K, Hirata Y. Genetic and epigenetic inactivation of mitotic checkpoint genes hBUB1 and hBUBR1 and their relationship to survival. Cancer Res. 2002 Jan 1;62(1):13-7 Warren CD, Brady DM, Johnston RC, Hanna JS, Hardwick KG, Spencer FA. Distinct chromosome segregation roles for spindle checkpoint proteins. Mol Biol Cell. 2002 Sep;13(9):3029-41 Hempen PM, Kurpad H, Calhoun ES, Abraham S, Kern SE. A double missense variation of the BUB1 gene and a defective 10 BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast)) Bolanos-Garcia VM, Blundell TL mitotic spindle checkpoint in the pancreatic cancer cell line Hs766T. Hum Mutat. 2003 Apr;21(4):445 through direct interaction with Bub1 and BubR1. Dev Cell. 2007 Nov;13(5):663-76 Johnson VL, Scott MI, Holt SV, Hussein D, Taylor SS. Bub1 is required for kinetochore localization of BubR1, Cenp-E, CenpF and Mad2, and chromosome congression. J Cell Sci. 2004 Mar 15;117(Pt 8):1577-89 Wong OK, Fang G. Cdk1 phosphorylation of BubR1 controls spindle checkpoint arrest and Plk1-mediated formation of the 3F3/2 epitope. J Cell Biol. 2007 Nov 19;179(4):611-7 Kang J, Yang M, Li B, Qi W, Zhang C, Shokat KM, Tomchick DR, Machius M, Yu H. Structure and substrate recruitment of the human spindle checkpoint kinase Bub1. Mol Cell. 2008 Nov 7;32(3):394-405 Vanoosthuyse V, Valsdottir R, Javerzat JP, Hardwick KG. Kinetochore targeting of fission yeast Mad and Bub proteins is essential for spindle checkpoint function but not for all chromosome segregation roles of Bub1p. Mol Cell Biol. 2004 Nov;24(22):9786-801 Bolanos-Garcia VM, Kiyomitsu T, D'Arcy S, Chirgadze DY, Grossmann JG, Matak-Vinkovic D, Venkitaraman AR, Yanagida M, Robinson CV, Blundell TL. The crystal structure of the N-terminal region of BUB1 provides insight into the mechanism of BUB1 recruitment to kinetochores. Structure. 2009 Jan 14;17(1):105-16 Lampson MA, Kapoor TM. The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments. Nat Cell Biol. 2005 Jan;7(1):93-8 Vaur S, Cubizolles F, Plane G, Genier S, Rabitsch PK, Gregan J, Nasmyth K, Vanoosthuyse V, Hardwick KG, Javerzat JP. Control of Shugoshin function during fission-yeast meiosis. Curr Biol. 2005 Dec 20;15(24):2263-70 McGuinness BE, Anger M, Kouznetsova A, Gil-Bernabé AM, Helmhart W, Kudo NR, Wuensche A, Taylor S, Hoog C, Novak B, Nasmyth K. Regulation of APC/C activity in oocytes by a Bub1-dependent spindle assembly checkpoint. Curr Biol. 2009 Mar 10;19(5):369-80 Wong OK, Fang G. Loading of the 3F3/2 antigen onto kinetochores is dependent on the ordered assembly of the spindle checkpoint proteins. Mol Biol Cell. 2006 Oct;17(10):4390-9 Bolanos-Garcia VM, Blundell TL. BUB1 and BUBR1: multifaceted kinases of the cell cycle. Trends Biochem Sci. 2011 Mar;36(3):141-50 Boyarchuk Y, Salic A, Dasso M, Arnaoutov A. Bub1 is essential for assembly of the functional inner centromere. J Cell Biol. 2007 Mar 26;176(7):919-28 This article should be referenced as such: Bolanos-Garcia VM, Blundell TL. BUB1 (budding uninhibited by benzimidazoles 1 homolog (yeast)). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):7-11. Kiyomitsu T, Obuse C, Yanagida M. Human Blinkin/AF15q14 is required for chromosome alignment and the mitotic checkpoint Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 11 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed) Mark Pickard Institute for Science and Technology in Medicine, Huxley Building, Keele University, Keele, ST5 5BG, UK (MP) Published in Atlas Database: July 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/FAUID40538ch11q13.html DOI: 10.4267/2042/47260 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology regulation, respectively. In human cells, ectopic FAU expression enhances basal apoptosis, whereas siRNAmediated silencing of FAU gene expression induces resistance to apoptosis induction in response to a range of stimuli. FAU gene expression is down-regulated in a number of human cancers, including breast, prostate and ovarian cancers. Identity Other names: FAU1, FLJ22986, Fub1, Fubi, MNSFbeta, RPS30, asr1 HGNC (Hugo): FAU Location: 11q13.1 Local order: FAU is flanked by SYVN1 and ZNHIT2 on the negative strand. Note FAU was originally identified as the cellular homologue of the fox gene of the retrovirus FinkelBiskis-Reilly murine sarcoma virus (FBR-MuSV); fox is antisense to FAU, and has been shown to increase the tumorigenicity of FBR-MuSV. FAU encodes a ubiquitin-like protein fused to ribosomal protein S30 as a carboxy-terminal extension; the two products are thought to be cleaved post-translationally. The S30 protein is a member of the S30E family of ribosomal proteins and is a constituent of the 40S subunit of the ribosome; additionally it is secreted and has antimicrobial activity ('ubiquicidin'). The function of the ubiquitin-like protein, termed FUBI, is unclear; in murine cells, it has been reported to covalently modify inter alia a T-cell receptor alpha-like protein and Bcl-G, suggestive of roles in immunomodulation and apoptosis DNA/RNA Description Gene is located on the negative strand at -64889908: 64887863 (2046 bases). The promoter contains a number of regulatory elements, including binding sites for transcription factors such as AP-1, IRF-1, Max, cMyc, glucocorticoid receptor isoforms and ATF. Transcription Comprises 5 exons spanning -64888099: -64889672. The mRNA product length is 579 bases. Pseudogene A retropseudogene, FAU1P, has been described in the human genome and is located on chromosome 18. Retropseudogenes of FAU have also been described in the mouse genome. FAU comprises 5 exons - the coding sequence for FUBI is located within exons 2 and 3, whereas the coding sequence for S30 is located within exons 4 and 5. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 12 FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed) Pickard M A. Protein products of FAU - FAU encodes a ubiquitin-like protein (FUBI) with ribosomal protein S30 as a C-terminal extension protein (CEP). These are cleaved post-translationally. B. FUBI has 37/57% sequence identity/similarity to ubiquitin (Ub; latter is fused to CEP80/S27a ribosomal protein). The C-terminal G-G dipeptide (shown in orange), which is required for cleavage from the CEP and for isopeptide bond formation to lysine of targets, is conserved. Note however, that lysine residues (shown in green) which serve as sites for polyubiquitin chain formation are absent. Consequently, FUBI is unlikely to have an analogous role to ubiquitin in protein degradation. of target proteins. Little information exists regarding target proteins for FUBI in human cells. In mouse, four target proteins have been identified. Covalent modification occurs for: (i) a T-cell receptor alpha-like protein (resulting in the production of murine monoclonal non-specific suppressor factor, which exhibits immunomodulatory activity); (ii) Bcl-G (a proapoptotic member of the Bcl-2 family; and (iii) endophilin II (regulates phagocytosis in mouse macrophages). Non-covalent modification of histone 2A has also been reported. Protein Description The protein product comprises a ubiquitin-like protein, FUBI, with ribosomal protein S30 as a carboxyterminal extension protein (CEP); other ribosomal proteins are produced as CEPs fused to ubiquitin. FUBI and S30 are thought to be cleaved post-translationally, but the enzyme catalyzing this step has not been identified. Whilst FUBI shows a high degree of sequence similarity to ubiquitin, notably retaining the C-terminal G-G dipeptide motif that is required for isopeptide bond formation between ubiquitin and lysines of target proteins, it lacks internal lysine residues (especially lysine-48) which serve as sites of polyubiquitin chain formation and usually facilitate proteasomal degradation of target molecules. Rather, modification of proteins with monomers of ubiquitin or ubiquitin-like proteins may influence the activity, intracellular localisation or inter-molecular interactions Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Expression Steady state FAU mRNA levels are highly abundant and largely invariant in normal tissues indicative of a house-keeping gene role. However, physiological variations occur in FAU expression, notably in endometrium. FAU transcript levels have been reported to be reduced in a number of human cancers, including those affecting the breast, the prostate and the ovary. 13 FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed) mitogen-stimulated T- and B-cells, immunoglobulin secretion by B-cells in an isotype-specific manner (IgE and IgG3 are especially affected), TNFalpha production by activated macrophages and interleukin-4 secretion by bone marrow-derived mast cells and by a type-2 helper T-cell clone (Nakamura et al., 1988; Nakamura et al., 1994; Xavier et al., 1994; Nakamura et al., 1995; Xavier et al., 1995; Nakamura et al., 1996; Suzuki et al., 1996). Inhibitory effects on T- and B-cell proliferation are subject to negative regulation by interleukin-2 (Nakamura et al., 1988). Many of these immunosuppresive effects of MNSF can be ascribed to the MNSFbeta subunit, and specifically to FUBI (aka Ubi-L) (Nakamura et al., 1996). Cell surface receptors for MNSF have been described in target cells (Nakamura et al., 1992), and these exhibit similarities to cytokine receptors (Nakamura and Tanigawa, 1999), with tyrosine phosphorylation being implicated in transmembrane signalling (Nakamura and Tanigawa, 2000; Nakamura et al., 2002). Both the expression of cell surface receptors on target cells and the secretion of MNSFbeta/FUBI by splenocytes are stimulated by interferon-gamma (Nakamura et al., 1992; Nakamura et al., 1996). In splenocytes, FUBI conjugates to a range of intracellular proteins, including a T-cell receptoralpha-like molecule; the resulting complex, which comprises intact MNSF, is secreted by cells (Nakamura et al., 1998; Nakamura et al., 2002). FUBI also covalently modifies Bcl-G in spleen but not in testis, despite high levels of Bcl-G expression in the latter tissue (Nakamura and Tanigawa, 2003). In macrophages, the FUBI/Bcl-G adduct binds to ERKs and inhibits ERK activation by MEK1 (Nakamura and Yamaguchi, 2006). In liver and macrophages, FUBI also forms an adduct with endophilin II and inhibits phagocytosis by macrophages (Nakamura and Shimosaki, 2009; Nakamura and Watanabe, 2010). Host defence An anti-microbial protein, termed ubiquicidin, has been isolated from the cytosol of a mouse macrophage cell line treated with interferon-gamma; the protein is active against Listeria monocytogenes, Salmonella typhimurium, Escherichia coli, Staphylococcus aureus and Yersinia enterocolitica (Hiemstra et al., 1999). Ubiquicidin is identical to FAU-encoded ribosomal protein S30 (Hiemstra et al., 1999). Ubiquicidin is also produced by human colonic mucosa (Tollin et al., 2003) and rainbow trout skin (Fernandes and Smith, 2002). It is also active against methicillin-resistant Staphylococcus aureus and accumulates at sites of infection in mice (Brouwer et al., 2006). Radiolabelled ubiquicidin has applications in clinical imaging for microbial infections (Brouwer et al., 2008). Localisation Cytosolic, ribosomal and nuclear localisations have been reported for FAU products. In addition, secretion of FUBI (in association with a T-cell receptor-alphalike molecule) has been reported for some immune system cell types. Function FAU regulates apoptosis in human epithelial and T-cell lines. It also possesses immunomodulatory and antimicrobial activities, and encodes a constituent of the ribosome. Regulation of apoptosis Functional expression cloning in mouse leukemic cell lines, with selection (dexamethasone and gammairradiation) for suppression of cell death, led to the isolation of a sequence which was antisense to FAU (Mourtada-Maarabouni et al., 2004). Subcloning experiments confirmed that this antisense sequence produced resistance to apoptosis induced by dexamethasone and, additionally, by cisplatin and by ultraviolet-C irradiation. The antisense sequence reduced endogenous FAU expression. Conversely, overexpression of FAU promoted cell death, and this effect could be prevented by co-transfection with a plasmid encoding Bcl-2 (an anti-apoptotic factor) or by inhibition of caspases. Further work in human T-cell lines and the epithelial cell line, 293T/17, has confirmed that ectopic FAU expression increases basal apoptosis, and that siRNA-mediated silencing of FAU attenuates apoptosis in response to ultraviolet-C irradiation (Pickard et al., 2011). FAU also regulates apoptosis in other human epithelial cell lines derived from breast (Pickard et al., 2009), ovarian (Moss et al., 2010) and prostate (Pickard et al., 2010) tumours (see 'Implicated in'). FUBI has been shown to covalently modify Bcl-G (a pro-apoptotic member of the Bcl-2 family) in mouse cells (Nakamura and Tanigawa, 2003), and it is feasible therefore, that FAU regulates apoptosis via Bcl-G. Indeed, prior knockdown of Bcl-G ablated the stimulation of basal apoptosis by FAU in human cells (Pickard et al., 2011). This pro-apoptotic activity may underlie the putative tumour suppressor role of FAU, since failure of apoptosis is known to play a central role in the development of many cancers. Immunomodulation Monoclonal non-specific suppressor factor (MNSF) was first isolated from mouse cells in 1986 (Nakamura et al., 1988) and subsequently, from ascites fluid of a patient with systemic lupus erythematosus (Xavier et al., 1994); most studies of MNSF to-date have focussed on murine cells. This lymphokine-like molecule, which comprises alpha- and beta-chains, is secreted by CD8+ T-cells (Xavier et al., 1995). cDNA encoding MNSFbeta was first isolated from the mouse in 1995, and it was shown to be identical to FAU (Nakamura et al., 1995). MNSF inhibits, inter alia, proliferation of Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Pickard M Homology At the amino acid level, FUBI has 37/57% sequence identity/similarity to ubiquitin. 14 FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed) Pickard M Implicated in simultaneously silenced, consistent with a role for BclG in mediating the pro-apoptotic activity of FAU. Various cancers Ovarian cancer Note Tumor suppression: The retrovirus, FBR-MuSV, which contains the transduced genes v-fos and fox, can induce osteosarcomas in mice. In vitro experiments have shown that fox increases the transforming capacity of FBR-MuSV approximately two-fold (Michiels et al., 1993). Fox is an antisense sequence to the cellular gene FAU, indicative of a tumour suppressor role for FAU. Retropseudogenes of FAU have been identified in human (Kas et al., 1995) and mouse (Casteels et al., 1995) genomes, suggesting a possible source for the viral fox gene (which is antisense to FAU). Further evidence for a tumour suppressor role for FAU has come from studies of the human carcinogen arsenite. Thus, functional cloning approaches in Chinese hamster V79 cells with selection for arsenite resistance, resulted in the isolation of the asr1 gene, which is homologous to FAU (Rossman and Wang, 1999). Subsequent work by this group using human osteogenic sarcoma cells, indicated that the ability to confer arsenite resistance resided in the S30 domain of FAU (Rossman et al., 2003). Oncogenesis Expression of the FUBI domain of FAU has been shown to transform human osteogenic sarcoma cells to anchorage-independent growth (Rossman et al., 2003). Note A reduction in FAU gene expression has been reported for malignant versus normal ovarian tissue, and for Type I ovarian tumours (typically include mucinous, endometrioid, clear cell, and low-grade serous cancers), in particular (Moss et al., 2010). Over-expression of FAU in a cisplatin-resistant ovarian cancer cell subline, A2780cis, resulted in increased sensitivity to carboplatin-induced apoptosis (Moss et al., 2010). Conversely, down-regulation of FAU in the A2780 parental cell line resulted in increased resistance to carboplatin-induced apoptosis (Moss et al., 2010). These in vitro findings suggest a role for FAU in the regulation of platinum-based drug resistance in ovarian cancer. Prostate cancer Note Steady state FAU mRNA levels are down-regulated in prostate cancer when compared with normal tissue and tissue from patients with benign prostate hyperplasia; a similar trend was found for Bcl-G (Pickard et al., 2010). siRNA-mediated silencing of FAU or Bcl-G expression in the prostate cell line, 22Rv1, attenuated apoptosis induction consequent upon ultraviolet-C irradiation. A similar degree of apoptosis resistance was observed when the two genes were simultaneously down-regulated, consistent with FAU and Bcl-G acting in the same pathway. Breast cancer Note Serial analysis of gene expression (SAGE) identified FAU as an underexpressed gene in ductal carcinoma in situ when compared with normal breast epithelium (Abba et al., 2004). This was subsequently confirmed using quantitative RT-PCR analysis of matched (same patient) samples of breast cancer tissue and adjacent breast epithelial tissue (Pickard et al., 2009). Furthermore, in a separate group of breast cancer patients, expression levels of FAU (determined by cDNA microarray analysis) were shown to be related to patient survival in Kaplan-Meier analyses (Pickard et al., 2009). This analysis indicated that higher expression of Fau has a protective effect, consistent with its candidate tumour suppressor role. Whilst Bcl-G expression was also shown to be down-regulated in breast cancer, Bcl-G expression was not related to patient survival (Pickard et al., 2009), suggesting that the regulation of Bcl-G activity by post-translational modification is more important than Bcl-G expression per se in determining breast cancer patient survival. Functional studies in the T-47D breast cancer cell line demonstrated that down-regulation of either FAU or Bcl-G expression by siRNA-mediated silencing attenuated apoptosis induction by ultraviolet-C irradiation (Pickard et al., 2009). Notably, no additional effect was observed when the two genes were Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Reproduction (implantation) Note FAU is expressed in endometrial stromal cells in nonpregnant mouse uterus (Salamonsen et al., 2002) and it is also expressed in human endometrium (Nie et al., 2005). In the mouse uterus, differential expression of FAU occurs during blastocyst implantation, with low expression levels noted in implantation versus interimplantation sites (Nie et al., 2000). Expression levels remain low as implantation advances (Nie et al., 2000). Administration of antisera to FAU into the mouse uterine lumen inhibits implantation in a dosedependent manner (Wang et al., 2007), suggesting an essential role for secreted products in implantation. Trophoblast-derived interferons have been shown to induce endometrial FAU expression in pigs (Chwetzoff and d'Andrea, 1997), also supporting an important role for FAU in early pregnancy. Breakpoints Note A t(11;14)(q13;q21)-positive B-cell non-Hodgkin's lymphoma patient has been described with an additional translocation of t(11;17)(q13;q21). The 15 FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed) Nakamura M, Xavier RM, Tsunematsu T, Tanigawa Y. Molecular cloning and characterization of a cDNA encoding monoclonal nonspecific suppressor factor. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3463-7 chromosome 11 breakpoint in the latter translocation was reported as a 40 kbp region around FAU. References Xavier R, Nakamura M, Kobayashi S, Ishikura H, Tanigawa Y. Human nonspecific suppressor factor (hNSF): cell source and effects on T and B lymphocytes. Immunobiology. 1995 Feb;192(3-4):262-71 Nakamura M, Ogawa H, Tsunematsu T. Isolation and characterization of a monoclonal nonspecific suppressor factor (MNSF) produced by a T cell hybridoma. J Immunol. 1986 Apr 15;136(8):2904-9 Nakamura M, Nagata T, Xavier M, Tanigawa Y. Ubiquitin-like polypeptide inhibits the IgE response of lipopolysaccharideactivated B cells. Int Immunol. 1996 Nov;8(11):1659-65 Nakamura M, Ogawa H, Tsunematsu T. Mode of action of monoclonal-nonspecific suppressor factor (MNSF) produced by murine hybridoma. Cell Immunol. 1988 Oct 1;116(1):230-9 Nakamura M, Xavier RM, Tanigawa Y. Ubiquitin-like moiety of the monoclonal nonspecific suppressor factor beta is responsible for its activity. J Immunol. 1996 Jan 15;156(2):5328 Nakamura M, Ogawa H, Tsunematsu T. Characterization of cell-surface receptors for monoclonal-nonspecific suppressor factor (MNSF). Cell Immunol. 1990 Oct 15;130(2):281-90 Suzuki K, Nakamura M, Nariai Y, Dekio S, Tanigawa Y. Monoclonal nonspecific suppressor factor beta (MNSF beta) inhibits the production of TNF-alpha by lipopolysaccharideactivated macrophages. Immunobiology. 1996 Jul;195(2):18798 Kas K, Michiels L, Merregaert J. Genomic structure and expression of the human fau gene: encoding the ribosomal protein S30 fused to a ubiquitin-like protein. Biochem Biophys Res Commun. 1992 Sep 16;187(2):927-33 Nakamura M, Ogawa H, Tsunematsu T. IFN-gamma enhances the expression of cell surface receptors for monoclonal nonspecific suppressor factor. Cell Immunol. 1992 Jan;139(1):131-8 Chwetzoff S, d'Andrea S. Ubiquitin is physiologically induced by interferons in luminal epithelium of porcine uterine endometrium in early pregnancy: global RT-PCR cDNA in place of RNA for differential display screening. FEBS Lett. 1997 Mar 24;405(2):148-52 Kas K, Schoenmakers E, van de Ven W, Weber G, Nordenskjöld M, Michiels L, Merregaert J, Larsson C. Assignment of the human FAU gene to a subregion of chromosome 11q13. Genomics. 1993 Aug;17(2):387-92 Nagata T, Nakamura M, Kawauchi H, Tanigawa Y. Conjugation of ubiquitin-like polypeptide to intracellular acceptor proteins. Biochim Biophys Acta. 1998 Mar 5;1401(3):319-28 Michiels L, Van der Rauwelaert E, Van Hasselt F, Kas K, Merregaert J. fau cDNA encodes a ubiquitin-like-S30 fusion protein and is expressed as an antisense sequence in the Finkel-Biskis-Reilly murine sarcoma virus. Oncogene. 1993 Sep;8(9):2537-46 Nakamura M, Tanigawa Y. Ubiquitin-like polypeptide conjugates to acceptor proteins in concanavalin A- and interferon gamma-stimulated T-cells. Biochem J. 1998 Mar 1;330 ( Pt 2):683-8 Olvera J, Wool IG. The carboxyl extension of a ubiquitin-like protein is rat ribosomal protein S30. J Biol Chem. 1993 Aug 25;268(24):17967-74 Nakamura M, Tsunematsu T, Tanigawa Y. TCR-alpha chainlike molecule is involved in the mechanism of antigen-nonspecific suppression of a ubiquitin-like protein. Immunology. 1998 Jun;94(2):142-8 Wlodarska I, Schoenmakers E, Kas K, Merregaert J, Lemahieu V, Weier U, Van den Berghe H, Van de Ven WJ. Molecular mapping of the chromosome 11 breakpoint of t(11;17)(q13;q21) in a t(11;14)(q13;q32)-positive B nonHodgkin's lymphoma. Genes Chromosomes Cancer. 1993 Dec;8(4):224-9 Hiemstra PS, van den Barselaar MT, Roest M, Nibbering PH, van Furth R. Ubiquicidin, a novel murine microbicidal protein present in the cytosolic fraction of macrophages. J Leukoc Biol. 1999 Sep;66(3):423-8 Kondoh T, Nakamura M, Nabika T, Yoshimura Y, Tanigawa Y. Ubiquitin-like polypeptide inhibits the proliferative response of T cells in vivo. Immunobiology. 1999 Feb;200(1):140-9 Nakamura M, Xavier RM, Tanigawa Y. Monoclonal nonspecific suppressor factor (MNSF) inhibits the IL4 secretion by bone marrow-derived mast cell (BMMC). FEBS Lett. 1994 Feb 21;339(3):239-42 Nakamura M, Tanigawa Y. Biochemical analysis of the receptor for ubiquitin-like polypeptide. J Biol Chem. 1999 Jun 18;274(25):18026-32 Xavier RM, Nakamura M, Tsunematsu T. Isolation and characterization of a human nonspecific suppressor factor from ascitic fluid of systemic lupus erythematosus. Evidence for a human counterpart of the monoclonal nonspecific suppressor factor and relationship to the T cell receptor alpha-chain. J Immunol. 1994 Mar 1;152(5):2624-32 Rossman TG, Wang Z. Expression cloning for arseniteresistance resulted in isolation of tumor-suppressor fau cDNA: possible involvement of the ubiquitin system in arsenic carcinogenesis. Carcinogenesis. 1999 Feb;20(2):311-6 Casteels D, Poirier C, Guénet JL, Merregaert J. The mouse Fau gene: genomic structure, chromosomal localization, and characterization of two retropseudogenes. Genomics. 1995 Jan 1;25(1):291-4 Nakamura M, Tanigawa Y. Protein tyrosine phosphorylation induced by ubiquitin-like polypeptide in murine T helper clone type 2. Biochem Biophys Res Commun. 2000 Aug 2;274(2):565-70 Kas K, Stickens D, Merregaert J. Characterization of a processed pseudogene of human FAU1 on chromosome 18. Gene. 1995 Jul 28;160(2):273-6 Nie GY, Li Y, Hampton AL, Salamonsen LA, Clements JA, Findlay JK. Identification of monoclonal nonspecific suppressor factor beta (mNSFbeta) as one of the genes differentially expressed at implantation sites compared to interimplantation sites in the mouse uterus. Mol Reprod Dev. 2000 Apr;55(4):351-63 Nakamura M, Xavier RM, Tanigawa Y. Monoclonal nonspecific suppressor factor beta inhibits interleukin-4 secretion by a type-2 helper T cell clone. Eur J Immunol. 1995 Aug;25(8):2417-9 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Pickard M 16 FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed) Fernandes JM, Smith VJ. A novel antimicrobial function for a ribosomal peptide from rainbow trout skin. Biochem Biophys Res Commun. 2002 Aug 9;296(1):167-71 Pickard M eradicate (multi-drug resistant) Staphylococcus aureus in mice. Peptides. 2006 Nov;27(11):2585-91 Nakamura M, Yamaguchi S. The ubiquitin-like protein MNSFbeta regulates ERK-MAPK cascade. J Biol Chem. 2006 Jun 23;281(25):16861-9 Nakamura M, Tsunematsu T, Tanigawa Y. Biochemical analysis of a T cell receptor alpha-like molecule involved in antigen-nonspecific suppression. Biochim Biophys Acta. 2002 Apr 3;1589(2):196-202 Salamonsen LA, Nie G, Findlay JK. Newly identified endometrial genes of importance for implantation. J Reprod Immunol. 2002 Jan;53(1-2):215-25 Wang J, Huang ZP, Nie GY, Salamonsen LA, Shen QX. Immunoneutralization of endometrial monoclonal nonspecific suppressor factor beta (MNSFbeta) inhibits mouse embryo implantation in vivo. Mol Reprod Dev. 2007 Nov;74(11):141927 Nakamura M, Tanigawa Y. Characterization of ubiquitin-like polypeptide acceptor protein, a novel pro-apoptotic member of the Bcl2 family. Eur J Biochem. 2003 Oct;270(20):4052-8 Brouwer CP, Wulferink M, Welling MM. The pharmacology of radiolabeled cationic antimicrobial peptides. J Pharm Sci. 2008 May;97(5):1633-51 Rossman TG, Visalli MA, Komissarova EV. fau and its ubiquitin-like domain (FUBI) transforms human osteogenic sarcoma (HOS) cells to anchorage-independence. Oncogene. 2003 Mar 27;22(12):1817-21 Nakamura M, Omura S. Quercetin regulates the inhibitory effect of monoclonal non-specific suppressor factor beta on tumor necrosis factor-alpha production in LPS-stimulated macrophages. Biosci Biotechnol Biochem. 2008 Jul;72(7):1915-20 Salamonsen LA, Dimitriadis E, Jones RL, Nie G. Complex regulation of decidualization: a role for cytokines and proteases--a review. Placenta. 2003 Apr;24 Suppl A:S76-85 Nakamura M, Shimosaki S. The ubiquitin-like protein monoclonal nonspecific suppressor factor beta conjugates to endophilin II and regulates phagocytosis. FEBS J. 2009 Nov;276(21):6355-63 Tollin M, Bergman P, Svenberg T, Jörnvall H, Gudmundsson GH, Agerberth B. Antimicrobial peptides in the first line defence of human colon mucosa. Peptides. 2003 Apr;24(4):523-30 Pickard MR, Green AR, Ellis IO, Caldas C, Hedge VL, Mourtada-Maarabouni M, Williams GT. Dysregulated expression of Fau and MELK is associated with poor prognosis in breast cancer. Breast Cancer Res. 2009;11(4):R60 Abba MC, Drake JA, Hawkins KA, Hu Y, Sun H, Notcovich C, Gaddis S, Sahin A, Baggerly K, Aldaz CM. Transcriptomic changes in human breast cancer progression as determined by serial analysis of gene expression. Breast Cancer Res. 2004;6(5):R499-513 Moss EL, Mourtada-Maarabouni M, Pickard MR, Redman CW, Williams GT. FAU regulates carboplatin resistance in ovarian cancer. Genes Chromosomes Cancer. 2010 Jan;49(1):70-7 Mourtada-Maarabouni M, Kirkham L, Farzaneh F, Williams GT. Regulation of apoptosis by fau revealed by functional expression cloning and antisense expression. Oncogene. 2004 Dec 16;23(58):9419-26 Nakamura M, Watanabe N. Ubiquitin-like protein MNSFβ/endophilin II complex regulates Dectin-1-mediated phagocytosis and inflammatory responses in macrophages. Biochem Biophys Res Commun. 2010 Oct 15;401(2):257-61 Nakamura M, Tanigawa Y. Ubiquitin-like polypeptide inhibits cAMP-induced p38 MAPK activation in Th2 cells. Immunobiology. 2004;208(5):439-44 Pickard MR, Edwards SE, Cooper CS, Williams GT. Apoptosis regulators Fau and Bcl-G are down-regulated in prostate cancer. Prostate. 2010 Oct 1;70(14):1513-23 Nakamura M, Tanigawa Y. Noncovalent interaction of MNSFbeta, a ubiquitin-like protein, with histone 2A. Comp Biochem Physiol B Biochem Mol Biol. 2005 Feb;140(2):207-10 Pickard MR, Mourtada-Maarabouni M, Williams GT. Candidate tumour suppressor Fau regulates apoptosis in human cells: an essential role for Bcl-G. Biochim Biophys Acta. 2011 Sep;1812(9):1146-53 Nie G, Findlay JK, Salamonsen LA. Identification of novel endometrial targets for contraception. Contraception. 2005 Apr;71(4):272-81 This article should be referenced as such: Pickard M. FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV) ubiquitously expressed). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):12-17. Brouwer CP, Bogaards SJ, Wulferink M, Velders MP, Welling MM. Synthetic peptides derived from human antimicrobial peptide ubiquicidin accumulate at sites of infections and Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 17 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Short Communication GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor)) Stephanie Schulz, Scott A Waldman Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA (SS, SAW) Published in Atlas Database: July 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/GUCY2CID43303ch12p13.html DOI: 10.4267/2042/47261 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Protein Other names: GUC2C, STAR HGNC (Hugo): GUCY2C Location: 12p13.1 Local order: ATF7IP - PLBD1 - GUCY2C - H2AFJ HIST4H4. Note GUCY2C encodes a guanylyl cyclase. DNA/RNA Expression Description Localisation The GUCY2C gene is approximately 84 kb in length and has 27 exons. Apical membrane. Description 1073 amino acid protein with guanylyl cyclase catalytic activity (4.6.1.2). Primarily intestinal epithelial cells. Function Transcription In response to binding endogenous hormones guanylin and uroguanylin, or the exogenous ligand E. coli heatstable enterotoxin, GUCY2C synthesizes cyclic GMP. Cyclic GMP activates downstream signaling pathways via cGMP-dependent protein kinases, phosphodiesterases and cGMP-gated ion channels. An approximately 3.8 mRNA is transcribed from the gene. Pseudogene None known. Homology Adenylyl cyclase. Image from NCBI. Image from Ensembl. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 18 GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor)) Schulz S, Waldman SA SP: signal peptide; ECD: extracellular ligand binding domain; TM: transmembrane domain; KHD: regulatory kinase-homology domain; CAT: guanylyl cyclase catalytic domain; TAIL: C-terminal tail, interacts with scaffolding proteins. Implicated in proliferating compartment in intestine. Am J Pathol. 2007 Dec;171(6):1847-58 Colorectal cancer Li P, Schulz S, Bombonati A, Palazzo JP, Hyslop TM, Xu Y, Baran AA, Siracusa LD, Pitari GM, Waldman SA. Guanylyl cyclase C suppresses intestinal tumorigenesis by restricting proliferation and maintaining genomic integrity. Gastroenterology. 2007 Aug;133(2):599-607 Note The endogenous GUCY2C ligands, guanylin and uroguanylin, are lost early in the neoplastic process. Targeted deletion of Gucy2c in mice results in a phenotype of intestinal cancer susceptibility in the context of predisposing genetic mutations (apcmin) or exposure to carcinogen (azoxymethane). Lin JE, Li P, Snook AE, Schulz S, Dasgupta A, Hyslop TM, Gibbons AV, Marszlowicz G, Pitari GM, Waldman SA. The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling. Gastroenterology. 2010 Jan;138(1):241-54 References This article should be referenced as such: Schulz S, Waldman SA. GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor)). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):18-19. Li P, Lin JE, Chervoneva I, Schulz S, Waldman SA, Pitari GM. Homeostatic control of the crypt-villus axis by the bacterial enterotoxin receptor guanylyl cyclase C restricts the Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 19 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review LIN28B (lin-28 homolog B (C. elegans)) Yung-Ming Jeng Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan (YMJ) Published in Atlas Database: July 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/LIN28BID45723ch6q16.html DOI: 10.4267/2042/47262 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Function Identity It inhibits biosynthesis of let-7 microRNA through promoting terminal uridylation of let-7 precusor by TUTase4. Other names: CSDD2, FLJ16517, Lin28.2 HGNC (Hugo): LIN28B Location: 6q16.3 Note Size: 146,72 kb. Orientation: plus strand. Homology Lin28 Mutations DNA/RNA Note No somatic mutation of Lin28B was identified in cancer. Description The gene spans over 125 kb on plus strand; 4 exons. Transcription Implicated in The gene is mainly expressed in fetal tissues and not expressed in adult tissue and reexpressed in cancer tissue. Hepatocellular carcinoma Note Lin28B expression is more frequently noted in highgrade hepatocellular carcinoma with high alphafetoprotein levels. Knockdown of Lin28B by RNA interference in the HCC cell line suppressed proliferation in vitro and reduced in vivo tumor growth in NOD/SCID mice. In contrast, overexpression of Lin28B in the HCC cell line enhanced tumorigenicity. Overexpression of Lin28B also induced epithelialmesenchymal transition in HA22T cells and hence, invasion capacity. Protein Description Lin28B is an oncofetal RNA-binding protein. Lin-28B protein consists of two domains that contain RNAbinding motif: the N-terminal cold shock domain and a pair of retroviral-type CCHC zinc fingers. It inhibits biosynthesis of let-7 microRNA through binding to the 5'-GGAG-3' motif in the terminal loop of pre-let-7 and promoting terminal uridylation of let-7 precusor by TUTase4. Uridylated pre-let-7 miRNAs fail to be processed by Dicer and undergo degradation. Colorectal cancer Note Lin28B is overexpressed in colorectal cancer. It promotes cell migration, invasion and transforms Expression Cytoplasm. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 20 LIN28B (lin-28 homolog B (C. elegans)) Jeng YM immortalized colonic epithelial cells. In addition, constitutive LIN28B expression increases expression of intestinal stem cell markers LGR5 and PROM1 in the presence of let-7 restoration. He C, Kraft P, Chen C, Buring JE, Paré G, Hankinson SE, Chanock SJ, Ridker PM, Hunter DJ, Chasman DI. Genomewide association studies identify loci associated with age at menarche and age at natural menopause. Nat Genet. 2009 Jun;41(6):724-8 Ovarian cancer Lu L, Katsaros D, Shaverdashvili K, Qian B, Wu Y, de la Longrais IA, Preti M, Menato G, Yu H. Pluripotent factor lin-28 and its homologue lin-28b in epithelial ovarian cancer and their associations with disease outcomes and expression of let-7a and IGF-II. Eur J Cancer. 2009 Aug;45(12):2212-8 Note Lin28B is overexpressed in high grade serous ovarian cancer. Pleomorphism in Lin28B promoter region is associated with susceptibility to epithelium ovarian cancer. Patients with high Lin28B ovarian cancer had shorter progression-free and overall survival than those with low Lin28B ovarian cancer. Viswanathan SR, Powers JT, Einhorn W, Hoshida Y, Ng TL, Toffanin S, O'Sullivan M, Lu J, Phillips LA, Lockhart VL, Shah SP, Tanwar PS, Mermel CH, Beroukhim R, Azam M, Teixeira J, Meyerson M, Hughes TP, Llovet JM, Radich J, Mullighan CG, Golub TR, Sorensen PH, Daley GQ. Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet. 2009 Jul;41(7):843-8 Age at menarche Note A sequence variation in Lin28B is identified as the SNP most significant associated with age at menarche in one genome wide study. Besides, a meta-analysis of 32 genome-wide association studies in 87802 women found polymorphism of Lin28B is strongly associated with age at menarche. Knockout mice of Lin28B also show delay in puberty onset. Helland Å, Anglesio MS, George J, Cowin PA, Johnstone CN, House CM, Sheppard KE, Etemadmoghadam D, Melnyk N, Rustgi AK, Phillips WA, Johnsen H, Holm R, Kristensen GB, Birrer MJ, Pearson RB, Børresen-Dale AL, Huntsman DG, deFazio A, Creighton CJ, Smyth GK, Bowtell DD. Deregulation of MYCN, LIN28B and LET7 in a molecular subtype of aggressive high-grade serous ovarian cancers. PLoS One. 2011 Apr 13;6(4):e18064 King CE, Cuatrecasas M, Castells A, Sepulveda AR, Lee JS, Rustgi AK. LIN28B promotes colon cancer progression and metastasis. Cancer Res. 2011 Jun 15;71(12):4260-8 Body height Note A LIN28B SNP, rs314277, is associated with final body height. King CE, Wang L, Winograd R, Madison BB, Mongroo PS, Johnstone CN, Rustgi AK. LIN28B fosters colon cancer migration, invasion and transformation through let-7-dependent and -independent mechanisms. Oncogene. 2011 Oct 6;30(40):4185-93 References This article should be referenced as such: Heo I, Joo C, Cho J, Ha M, Han J, Kim VN. Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Mol Cell. 2008 Oct 24;32(2):276-84 Jeng YM. LIN28B (lin-28 homolog B (C. elegans)). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):20-21. Viswanathan SR, Daley GQ, Gregory RI. Selective blockade of microRNA processing by Lin28. Science. 2008 Apr 4;320(5872):97-100 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 21 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review PKD1 (polycystic kidney disease 1 (autosomal dominant)) Ying-Cai Tan, Hanna Rennert Department of Pathology and Laboratory Medicine, Weill Cornell Medical College 1300 York Street, F701 New York, NY 10065, USA (YCT, HR) Published in Atlas Database: July 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/PKD1ID41725ch16p13.html DOI: 10.4267/2042/47263 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Transcription Identity The 14,5 kb transcript has two different isoforms as a result of alternative splicing. The longer variant, isoform I (NM_001009944), has a 12909 bp open reading frame. The short variant, isoform II (NM_000293), uses an alternate acceptor splice site, 3 nt downstream of that used by isoform I, at the junction of intron 31 and exon 32. This results in an isoform (variant II) that is one amino acid shorter than isoform I. Other names: PBP, Pc-1, polycystin-1, TRPP1 HGNC (Hugo): PKD1 Location: 16p13.3 DNA/RNA Description This gene has 46 exons that span ~52 kb of genomic sequence. Exons 1-33 are located in a genomic region which is duplicated six times on the same chromosome (~13-16 Mb proximal to PKD1 on the short arm of chromosome 16), resulting in six pseudogenes. A Mirtron family microRNA gene, miR-1225, is lying within intron 45 of PKD1, the function of this microRNA is currently unknown. Pseudogene The six pseudogenes that result from duplication of PKD1 exon 1 through 33 are located on chromosome 16p13.1 and have 97-99% identity to PKD1. Those pseudogenes are transcripted into mRNA species with suboptimal start codons, thus they are not translated. Ideogram of human chromosome 16, the location of PKD1 gene is indicated by the red vertical line. This graph was generated by using UCSC genome browser. Gene structure of PKD1, showing the intron/exon structure. Exons are shown with solid box; introns are shown with thin line arrow heads; 3' and 5' UTR regions are indicated by open boxes. Some exons numbers are labelled above. This graph was generated by using UCSC genome browser. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 22 PKD1 (polycystic kidney disease 1 (autosomal dominant)) Tan YC, Rennert H Protein structure of polycystin-1 (PC1). The details of the protein domain structures are shown. Abreviation: GPS, GPCR Proteolystic Site; WSC, cell Wall integrity and Stress response Component; PLAT, (Polycystin-1, Lipoxygenase, Alpha-Toxin); REJ, Receptor for Egg Jelly. This graph was generated by using ExPASY Proteomics Server PROSITE module with some modifications. Function Protein In the kidney tubule, polycystin-1 was shown to serve as a mechanoreceptor that senses fluid flow in the tubular lumen, triggering Ca2+ influx through polycystin-2, a Ca2+ channel that interact with PC1 in the C-terminal tail, consequently affecting the intracellular calcium and cyclic AMP (cAMP) levels. It is also involved in cell-to-cell or cell-to-matrix interactions. Description The longer form of polycystin-1, isoform I, has 4303 aa. It is a 460 kDa membrane protein which has the structure of a receptor or adhesion molecule. The large extracellular N-terminal region consisting of a variety of domains, including 12 PKD domains (an immunoglobin-like fold), two leucine-rich repeats, Ctype lectin domain, WSC domain, GPS domain and REJ domain. The short intracellular C-terminal region has 197 aa, containing a coiled-coil domain that interact with polycystin-2 and a G-protein binding domain. Between the N and C-terminal is a large transmembrane region (1032 aa) that has 11 transmembrane domains. Polycystin-1 is cleaved at the G protein-coupled receptor proteolytic site (GPS) domain, resulting in a 150 kDa C-terminal fragment and a 400 kDa N-terminal fragment that tether to the membrane. This cleavage is suggested to be important for protein activation. Homology The characterized domains of polycystin-1 are regions highly conserved among species (from human to fish). A homology and also an interaction partner in the same signaling passway, polycystin-2, is located on 4q21. Mutations Germinal Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease. Up to 85% of ADPKD cases are caused by mutations in PKD1 gene. With the current mutation detection methods, definite pathogenic mutations (nonsense, truncation and canonical splice defects) are identified in approximately 60% of the cases. Large deletions/insertions can be found in ~4% of cases. Comprehensive analyses, using bioinformatics analysis tools can identify missense mutations that may account for the disease in an additional 22% to 37% of the ADPKD patients. There are no mutation hot spots for PKD1, which means mutations are usually private, with 70% of the mutations unique to a single family, and spread throughout the entire gene. Mutations on 5' of the gene are associated with a more sever disease compared to those occurring in 3' region. The ADPKD Mutation Database at Mayo Clinic (http://pkdb.mayo.edu/), the most complete one for Expression Polycystin-1 is widely expressed in adult tissue, with high levels in brain and moderate expression in kidney. In fetal and adult kidney, the expression was restricted to the epithelial cells with highest expression in the embryo and downregulation in adult. In smooth, skeletal and cardiac muscles, expression is also found. Localisation Polycystin-1 is located in the primary cilium, a single hair-like organelle projecting from the surface of most mammalian cells. It is also found in the plasma membrane at focal adhesions, desmosomes, and adherens junctions. The C-terminal tail of PC1 has been reported to be cleaved and migrate to the nucleus, regulating gene expression. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 23 PKD1 (polycystic kidney disease 1 (autosomal dominant)) Tan YC, Rennert H ADPKD, documents 416 pathogenic mutations for PKD1 in a total of 616 families. enlarged, cystic kidneys to incidental diagnosis in the elderly with adequate renal function. Extra-renal manifestations include cysts in the liver, pancreas, seminal vesicles and arachnoid membranes. Intracranial aneurysm is about five times more common than in the general population and is associated with significant morbidity and mortality. Prognosis About 50% of patients with ADPKD will progress to end stage renal disease (ESRD) by the age of 60 years, with hemodialysis or kidney transplant being the only currently available treatment, though several potential drugs have been entered into clinical trials. Hypertension is present in about 50% of ADPKD patients age 20-30 years with clinically normal renal function; this is approximately one decade earlier than the onset of primary hypertension in the general population. Somatic The pathogenesis of ADPKD has been attributed to a two-hit mechanism, with somatic and germline mutations combining to inactivate one of the PKD genes, leading to loss of function, thus initiating the disease process. There are significantly less somatic PKD mutations listed in the ADPKD Mutation Database, only 9 for PKD1 (http://pkdb.mayo.edu/). Due to the limited availability of kidney cyst DNA and the complications associated with PKD1 genotyping, analyzing somatic mutations in ADPKD was proven to be difficult. Implicated in Autosomal dominant polycystic kidney disease (ADPKD) References Disease ADPKD is a monogenic multi-systemic disorder characterized by age-dependent development and progressive enlargement of bilateral, multiple renal cysts, resulting in chronic renal failure typically in mid to late adulthood. The cysts are caused by abnormal proliferation of renal tubule epithelial cells as a result of inactivation of the PKD genes by mutations. Mutations in PKD1 gene account for 85% of the ADPKD cases and for the early-onset, more sever form. Those cysts will increase gradually in both size and number, leading to massive kidney enlargement and progressive decline in renal function. ADPKD has a prevalence of approximately 1 in 400 to 1 in 1000 live births in all races, affecting approximately 12,5 million individuals worldwide. Although ADPKD accounts for 4,4% of all patients requiring renal replacement therapy, it is characterized by very large phenotypic variability, ranging from presentation inutero with Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Wilson PD. Polycystic kidney disease. N Engl J Med. 2004 Jan 8;350(2):151-64 Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007 Apr 14;369(9569):1287-301 Tan YC, Blumenfeld JD, Anghel R, Donahue S, Belenkaya R, Balina M, Parker T, Levine D, Leonard DG, Rennert H. Novel method for genomic analysis of PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease. Hum Mutat. 2009 Feb;30(2):264-73 Torres VE, Harris PC. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int. 2009 Jul;76(2):149-68 Harris PC, Rossetti S. Molecular diagnostics for autosomal dominant polycystic kidney disease. Nat Rev Nephrol. 2010 Apr;6(4):197-206 This article should be referenced as such: Tan YC, Rennert H. PKD1 (polycystic kidney disease 1 (autosomal dominant)). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):22-24. 24 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review AMFR (autocrine motility factor receptor) Yalcin Erzurumlu, Petek Ballar Ege University, Faculty of Pharmacy, Biochemistry Department, Bornova, 35100, Izmir, Turkey (YE, PB) Published in Atlas Database: August 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/AMFRID627ch16q12.html DOI: 10.4267/2042/47264 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity strand. The DNA of AMFR consists of 14 exons and the coding sequence starts in the first exon. Other names: GP78, RNF45 HGNC (Hugo): AMFR Location: 16q12.2 Transcription The AMFR gene has two transcripts. One of these transcripts is 2249 bp long and is a processed transcript with no protein product. 3598 bp long second AMFR transcript is a protein coding transcript (accession number: NM_001144). The DNA has been cloned in 1999 (Shimizu et al., 1999). DNA/RNA Description The AMFR gene spans 64081 bases on minus AMFR gene genomic location at chromosome 16q12.2 (minus strand). A. The alignment of AMFR mRNA to its genomic sequence. B. AMFR mRNA and its amino acid coding. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 25 AMFR (autocrine motility factor receptor) Erzurumlu Y, Ballar P A schematic representation of the domain structure. Expression Protein gp78/AMFR is relatively ubiquitously expressed in normal human cells, especially highly in liver, heart and lung. Northern blot analysis detected a 3.5-kb AMFR transcript in mouse heart, brain, lung, liver, skeletal muscle, kidney, and testis, but not in spleen (Shimizu et al., 1999). gp78/AMFR is overexpressed in certain malignant tumors and human cancers of the lung, gastrointestinal tract, breast, liver, thymus, and skin (Chiu et al., 2008; Sjöblom et al., 2006; Tsai et al., 2007; Joshi et al., 2010). Description AMFR belongs to the family of RING-Finger ubiquitin ligases. The complete protein contains 643 amino acids. The calculated molecular weight of AMFR is 73,0 kDa. AMFR was originally isolated as a membrane glycoprotein from murine melanoma cells and was implicated in cell migration (Nabi and Raz, 1987). Subsequently, gp78/AMFR was identified as the tumor autocrine motility factor receptor mediating tumor invasion and metastasis (Nabi et al., 1990). A monoclonal antibody named 3F3A was generated against this protein and first sequence reported for human gp78/AMFR was in 1991 using this antibody (Watanabe et al., 1991). However, the protein product was only 321 amino acids (Watanabe et al., 1991). A sequence giving 643 amino acids protein product was cloned in 1999 (Shimizu et al., 1999). gp78/AMFR has five to seven transmembrane domains according to different softwares like SACS MEMSAT and SOSUI. The protein has a long cytoplasmic tail composed of around 350 amino acids (Shimizu et al., 1999). Besides conveying E3 activity the multifunctional cytoplasmic tail is responsible for interaction with polyubiquitin, ubiquitin conjugating enzyme, p97/VCP and Ufd1. The RING finger domain of gp78/AMFR residing between amino acids 341 and 383 is a RING-H2 type domain containing two His residues in positions 4 and 5 (Fang et al., 2001). The Cue domain of gp78/AMFR residing between amino acids 456 and 497 is responsible for polyubiquitin binding and has been identified by having homologous sequences of yeast protein Cue1p (Ponting, 2000). The p97/VCP-interacting motif of gp78/AMFR consists of C-terminal amino acid residues between 614-643 and it is sufficient to bind to p97/VCP protein (Ballar et al., 2006). gp78/AMFR binds to its ubiquitin conjugating enzyme via a region called UBE2G2 binding region (G2BR) and this region is resides between amino acids 579 and 600 (Chen et al., 2006). Additionally, gp78/AMFR interacts directly with Ufd1 through residues 383-497 (Cao et al., 2007) and with INSIGs through its transmembrane domains (Song et al., 2005). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Localisation Endoplasmic reticulum membrane, transmembrane protein (Fang et al., 2001). multi-pass Function In 2001, it has been reported that gp78/AMFR possesses ubiquitin ligase (E3) activity (Fang et al., 2001) and can ubiquitinate both itself and other proteins for proteasomal degradation. gp78/AMFR is a member of multiprotein complex functioning in endoplasmic reticulum associated degradation (ERAD). gp78/AMFR not only functions as an E3 during ERAD but also couples retrotranslocation and deglycosylation to ubiquitination (Ballar et al., 2006; Li et al., 2005). Homology Homologues have been found in various species like bovine, chimpanzee (99.8 % homology), chicken, zebra fish, rat, C. elegans and mouse. gp78/AMFR shares 94.7 % of homology with murine gp78/AMFR. Mutations Somatic D605V mutation has been reported in breast cancer (Sjöblom et al., 2006). Several SNPs have been found in gp78/AMFR gene both at coding regions and at UTRs and introns. See SNP database at NCBI. Implicated in Sarcoma metastasis Note gp78/AMFR targets KAI1, a known metastasis 26 AMFR (autocrine motility factor receptor) Erzurumlu Y, Ballar P suppressor protein for ubiquitin mediated proteasomal degradation (Tsai et al., 2007). Thus gp78/AMFR has role in metastasis of human sarcoma. Furthermore, a human sarcoma tissue microarray study documents that tumors with low gp78 expression has higher levels of KAI1 and high gp78 level lower KAI1 expression in tumors (Tsai et al., 2007). pericarcinomatous liver tissues. Furthermore, there is a strong correlation between AMFR expression and invasion and metastasis of HCC (Wang et al., 2007). Bladder carcinoma Note While in normal urothelium gp78/AMFR is not expressed, its expression is increased in bladder carcinoma specimens (Otto et al., 1994). Breast cancer Note gp78/AMFR expression in gp78 transgenic mammary glands induces mammary gland hyperplasia, increases duct number and network density and shows downregulation of KAI1 metastasis suppressor (Joshi et al., 2010). Additionally, gp78/AMFR has been identified as one of the most mutated genes in breast cancer (Sjöblom et al., 2006). Consistently, gp78/AMFR is overexpressed in human breast cancer and is negatively associated with patients' clinical outcome (Jiang et al., 2006). Cardiovascular diseases and hypercholesterolemia Note Accumulation of sterols in ER membranes triggers the binding of HMG CoA reductase, the rate limiting enzyme of cholesterol biosynthesis, to the Insig1gp78/AMFR complex which is essential for the ubiquitination and proteasomal degradation of HMGCoA-reductase (Goldstein et al., 2006; Jo and DeBose-Boyd, 2010). gp78/AMFR is also the E3 ligase of apolipoprotein B100, the protein component of atherogenic lipoproteins, overproduction of which is a common feature of human dyslipidemia (Liang et al., 2003). Gastric carcinoma Note gp78/AMFR expression may be associated with the progression and invasion of gastric carcinoma as well as the prognoses of the patients (Hirono et al., 1996). Furthermore, by using same 3F3A antibody it was reported that gp78/AMFR expression is associated with lymph node metastasis and peritoneal dissemination in gastric carcinoma (Taniguchi et al., 1998). Cystic fibrosis Note gp78/AMFR degrades mutant cystic fibrosis transmembrane conductance regulator (CFTR∆F508) associated with cystic fibrosis (Ballar et al., 2010; Morito et al., 2008). Colorectal cancer Metabolism and disposition of drugs Note gp78/AMFR expression is correlated high incidence of recurrence of the patients with colorectal cancer (Nakamori et al., 1994). Note gp78/AMFR participates in proteasomal degradation of CYP3A4, a dominant human liver cytochrome P450 enzyme functioning in the metabolism and disposition of drugs and responsible for many adverse drug-drug interactions (Kim et al., 2010; Pabarcus et al., 2009). Melanoma Note It was showed by using 3F3A antibody that gp78/AMFR protein expression in human melanoma cell lines correlates to their metastatic potential. While in thin tumors weak/heterogenous gp78/AMFR expression predominated, in thick tumors the strong gp78/AMFR expression profile was predominant (Tímár et al., 2002). Chronic obstructive pulmonary disease Note gp78/AMFR expression is increased with the severity of emphysema (Min et al., 2011). Neurodegenerative diseases Note gp78/AMFR may play a protective role against mutant huntingtin toxicity. Mutant huntingtin hinders polyubiquitin binding to the cue domain of gp78/AMFR and causes aggregation of ligase (Yang et al., 2010). gp78/AMFR also enhances ubiquitination, degradation, suppression of aggregation of mutant SOD1 associated with amyotrophic lateral sclerosis (ALS), and mutant ataxin-3 associated with MachadoJoseph disease. Furthermore, in spinal cords of ALS mice, gp78/AMFR expression is significantly is upregulated (Ying et al., 2009). Lung cancer Note Using immunohistochemical staining the gp78/AMFR expression was showed to be associated with histologic type of tumor, mainly in adenocarcinoma (Kara et al., 2001). Hepatocellular carcinoma Note The expression of gp78/AMFR significantly increased in hepatocellular carcinoma compared with Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 27 AMFR (autocrine motility factor receptor) Erzurumlu Y, Ballar P Liang JS, Kim T, Fang S, Yamaguchi J, Weissman AM, Fisher EA, Ginsberg HN. Overexpression of the tumor autocrine motility factor receptor Gp78, a ubiquitin protein ligase, results in increased ubiquitinylation and decreased secretion of apolipoprotein B100 in HepG2 cells. J Biol Chem. 2003 Jun 27;278(26):23984-8 Alpha-1-antitrypsin deficiency Note gp78/AMFR targets mutant ATZ (Z-variant alpha-1antitrypsin) associated with alpha-1-antitrypsin deficiency for the proteasomal degradation and increases its solubility (Shen et al., 2006). Li G, Zhou X, Zhao G, Schindelin H, Lennarz WJ. Multiple modes of interaction of the deglycosylation enzyme, mouse peptide N-glycanase, with the proteasome. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15809-14 References Song BL, Sever N, DeBose-Boyd RA. Gp78, a membraneanchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Mol Cell. 2005 Sep 16;19(6):829-40 Nabi IR, Raz A. Cell shape modulation alters glycosylation of a metastatic melanoma cell-surface antigen. Int J Cancer. 1987 Sep 15;40(3):396-402 Nabi IR, Watanabe H, Raz A. Identification of B16-F1 melanoma autocrine motility-like factor receptor. Cancer Res. 1990 Jan 15;50(2):409-14 Ballar P, Shen Y, Yang H, Fang S. The role of a novel p97/valosin-containing protein-interacting motif of gp78 in endoplasmic reticulum-associated degradation. J Biol Chem. 2006 Nov 17;281(46):35359-68 Watanabe H, Carmi P, Hogan V, Raz T, Silletti S, Nabi IR, Raz A. Purification of human tumor cell autocrine motility factor and molecular cloning of its receptor. J Biol Chem. 1991 Jul 15;266(20):13442-8 Chen B, Mariano J, Tsai YC, Chan AH, Cohen M, Weissman AM. The activity of a human endoplasmic reticulum-associated degradation E3, gp78, requires its Cue domain, RING finger, and an E2-binding site. Proc Natl Acad Sci U S A. 2006 Jan 10;103(2):341-6 Silletti S, Raz A. Autocrine motility factor is a growth factor. Biochem Biophys Res Commun. 1993 Jul 15;194(1):446-57 Nakamori S, Watanabe H, Kameyama M, Imaoka S, Furukawa H, Ishikawa O, Sasaki Y, Kabuto T, Raz A. Expression of autocrine motility factor receptor in colorectal cancer as a predictor for disease recurrence. Cancer. 1994 Oct 1;74(7):1855-62 Goldstein JL, DeBose-Boyd RA, Brown MS. Protein sensors for membrane sterols. Cell. 2006 Jan 13;124(1):35-46 Jiang WG, Raz A, Douglas-Jones A, Mansel RE. Expression of autocrine motility factor (AMF) and its receptor, AMFR, in human breast cancer. J Histochem Cytochem. 2006 Feb;54(2):231-41 Otto T, Birchmeier W, Schmidt U, Hinke A, Schipper J, Rübben H, Raz A. Inverse relation of E-cadherin and autocrine motility factor receptor expression as a prognostic factor in patients with bladder carcinomas. Cancer Res. 1994 Jun 15;54(12):3120-3 Shen Y, Ballar P, Fang S. Ubiquitin ligase gp78 increases solubility and facilitates degradation of the Z variant of alpha-1antitrypsin. Biochem Biophys Res Commun. 2006 Nov 3;349(4):1285-93 Hirono Y, Fushida S, Yonemura Y, Yamamoto H, Watanabe H, Raz A. Expression of autocrine motility factor receptor correlates with disease progression in human gastric cancer. Br J Cancer. 1996 Dec;74(12):2003-7 Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The consensus coding sequences of human breast and colorectal cancers. Science. 2006 Oct 13;314(5797):268-74 Taniguchi K, Yonemura Y, Nojima N, Hirono Y, Fushida S, Fujimura T, Miwa K, Endo Y, Yamamoto H, Watanabe H. The relation between the growth patterns of gastric carcinoma and the expression of hepatocyte growth factor receptor (c-met), autocrine motility factor receptor, and urokinase-type plasminogen activator receptor. Cancer. 1998 Jun 1;82(11):2112-22 Cao J, Wang J, Qi W, Miao HH, Wang J, Ge L, DeBose-Boyd RA, Tang JJ, Li BL, Song BL. Ufd1 is a cofactor of gp78 and plays a key role in cholesterol metabolism by regulating the stability of HMG-CoA reductase. Cell Metab. 2007 Aug;6(2):115-28 Shimizu K, Tani M, Watanabe H, Nagamachi Y, Niinaka Y, Shiroishi T, Ohwada S, Raz A, Yokota J. The autocrine motility factor receptor gene encodes a novel type of seven transmembrane protein. FEBS Lett. 1999 Aug 6;456(2):295300 Tsai YC, Mendoza A, Mariano JM, Zhou M, Kostova Z, Chen B, Veenstra T, Hewitt SM, Helman LJ, Khanna C, Weissman AM. The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation. Nat Med. 2007 Dec;13(12):1504-9 Ponting CP. Proteins of the endoplasmic-reticulum-associated degradation pathway: domain detection and function prediction. Biochem J. 2000 Oct 15;351 Pt 2:527-35 Wang W, Yang LY, Yang ZL, Peng JX, Yang JQ. Elevated expression of autocrine motility factor receptor correlates with overexpression of RhoC and indicates poor prognosis in hepatocellular carcinoma. Dig Dis Sci. 2007 Mar;52(3):770-5 Fang S, Ferrone M, Yang C, Jensen JP, Tiwari S, Weissman AM. The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14422-7 Chiu CG, St-Pierre P, Nabi IR, Wiseman SM. Autocrine motility factor receptor: a clinical review. Expert Rev Anticancer Ther. 2008 Feb;8(2):207-17 Kara M, Ohta Y, Tanaka Y, Oda M, Watanabe Y. Autocrine motility factor receptor expression in patients with stage I nonsmall cell lung cancer. Ann Thorac Surg. 2001 Mar;71(3):944-8 Morito D, Hirao K, Oda Y, Hosokawa N, Tokunaga F, Cyr DM, Tanaka K, Iwai K, Nagata K. Gp78 cooperates with RMA1 in endoplasmic reticulum-associated degradation of CFTRDeltaF508. Mol Biol Cell. 2008 Apr;19(4):1328-36 Tímár J, Rásó E, Döme B, Ladányi A, Bánfalvi T, Gilde K, Raz A. Expression and function of the AMF receptor by human melanoma in experimental and clinical systems. Clin Exp Metastasis. 2002;19(3):225-32 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 28 AMFR (autocrine motility factor receptor) Erzurumlu Y, Ballar P Pabarcus MK, Hoe N, Sadeghi S, Patterson C, Wiertz E, Correia MA. CYP3A4 ubiquitination by gp78 (the tumor autocrine motility factor receptor, AMFR) and CHIP E3 ligases. Arch Biochem Biophys. 2009 Mar 1;483(1):66-74 Kim SM, Acharya P, Engel JC, Correia MA. Liver cytochrome P450 3A ubiquitination in vivo by gp78/autocrine motility factor receptor and C terminus of Hsp70-interacting protein (CHIP) E3 ubiquitin ligases: physiological and pharmacological relevance. J Biol Chem. 2010 Nov 12;285(46):35866-77 Ying Z, Wang H, Fan H, Zhu X, Zhou J, Fei E, Wang G. Gp78, an ER associated E3, promotes SOD1 and ataxin-3 degradation. Hum Mol Genet. 2009 Nov 15;18(22):4268-81 Yang H, Liu C, Zhong Y, Luo S, Monteiro MJ, Fang S. Huntingtin interacts with the cue domain of gp78 and inhibits gp78 binding to ubiquitin and p97/VCP. PLoS One. 2010 Jan 26;5(1):e8905 Ballar P, Ors AU, Yang H, Fang S. Differential regulation of CFTRDeltaF508 degradation by ubiquitin ligases gp78 and Hrd1. Int J Biochem Cell Biol. 2010 Jan;42(1):167-73 Min T, Bodas M, Mazur S, Vij N. Critical role of proteostasisimbalance in pathogenesis of COPD and severe emphysema. J Mol Med (Berl). 2011 Jun;89(6):577-93 Jo Y, Debose-Boyd RA. Control of cholesterol synthesis through regulated ER-associated degradation of HMG CoA reductase. Crit Rev Biochem Mol Biol. 2010 Jun;45(3):185-98 This article should be referenced as such: Joshi B, Li L, Nabi IR. A role for KAI1 in promotion of cell proliferation and mammary gland hyperplasia by the gp78 ubiquitin ligase. J Biol Chem. 2010 Mar 19;285(12):8830-9 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Erzurumlu Y, Ballar P. AMFR (autocrine motility factor receptor). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):25-29. 29 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review ASH2L (ash2 (absent, small, or homeotic)-like (Drosophila)) Paul F South, Scott D Briggs Department of Biochemistry and Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA (PFS, SDB) Published in Atlas Database: August 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/ASH2LID44404ch8p11.html DOI: 10.4267/2042/47265 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology 573 from isoform 1 (Wang et al., 2001). Isoform 3 is missing the amino acids 1-94 from isoform 1 (figure 2) (Wang et al., 2001). There are four identified domains within ASH2L which include a N-terminus containing a PHD finger and a winged helix motif (WH) and the C-terminus containing a SPRY domain and the Sdc1 DPY-30 Interacting domain (SDI) (figure 2) (Chen et al., 2011; Roguev et al., 2001; Sarvan et al., 2011; South et al., 2010; Wang et al., 2001). The largest of the three identified domains within ASH2L is the SPRY domain, which is also conserved from yeast to humans. SPRY domains were originally named after the SPIa kinase and the RYanodine receptor proteins in which it was first identified (Rhodes et al., 2005). Crystal structures of SPRY domain containing proteins show primarily a beta-sandwich structure with extending loops (Filippakopoulos et al., 2010; Kuang et al., 2009; Simonet et al., 2007; Woo et al., 2006b). The SPRY domain is thought to be a specific proteinprotein interaction domain Identity Other names: ASH2, ASH2L1, ASH2L2, Bre2 HGNC (Hugo): ASH2L Location: 8p11.23 DNA/RNA Description 16 exons spanning over 34218 base pairs. Transcription mRNA is 2368 base pairs long. Protein Description There are three known isoforms of ASH2L (Wang et al., 2001). Isoform 1 is considered the canonical sequence and consists of 628 amino acids (Wang et al., 2001). Isoform 2 is missing amino acids 1-94 and 541- Figure 1. Map of chromosome 8 with region 8p11.2 highlighted as the location of the gene ASH2L. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 30 ASH2L (ash2 (absent, small, or homeotic)-like (Drosophila)) South PF, Briggs SD Figure 2. Schematic model of the three known isoforms of ASH2L and the amino acid sequence changes compared to the canonical isoform 1 (aa 1-628). The positions of known domains within ASH2L are displayed. PHD finger (aa 95-161), WH motif (aa 162-273), SPRY domain (aa 360-583), and SDI domain (aa 602-628). Isoform 2 and 3 are numbered according to isoform 1. with specific partners, but instead of recognizing a particular motif or interaction domain the SPRY domain binds to interaction partners using nonconserved binding loops (Filippakopoulos et al., 2010; Woo et al., 2006a; Woo et al., 2006b). Recent work has shown that the C-terminus of ASH2L that contains the SPRY domain and the SDI domain are able to interact with the other MLL complex member RBBP5 in vitro (Avdic et al., 2011). ASH2L also contains a putative Plant Homeo Domain (PHD) finger in its N-terminus (Wang et al., 2001). The structure of PHD fingers shows that conserved cysteine and histidine residues bind to Zn2+ ions (Champagne et al., 2008; Champagne and Kutateladze, 2009; van Ingen et al., 2008). There is no known function attributed to the PHD finger in ASH2L, though in conjunction with the winged helix motif it may be necessary for DNA binding. The N-terminal winged helix (WH) motif was recently discovered when the crystal structure of the N-terminus of ASH2L was solved (Chen et al., 2011; Sarvan et al., 2011). Using in vitro DNA binding analyses as well as chromatin immunoprecipitation, it was determined that ASH2L can bind DNA at the HS2 promoter region and the beta-globin locus as well as non-specific DNA sequence (Chen et al., 2011; Sarvan et al., 2011). The last identifiable domain within ASH2L is the SDI domain. There is no structural information on the SDI domain but the functional importance was determined biochemically. The function of the SDI domain was determined using in vitro binding experiments. ASH2L was shown to directly interact with DPY-30 without any additional MLL or Set1 complex components (South et al., 2010). The function of the SDI domain is conserved from yeast to humans because the yeast ASH2L homolog Bre2 was also shown to interact with the DPY-30 homolog Sdc1 (South et al., 2010). There are conserved hydrophobic residues in both the SDI domain of ASH2L and the Dpy-30 domain of DPY-30 that are important for binding, which suggests that the Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) interaction between the SDI domain of ASH2L and the DPY-30 domain of DPY-30 is through hydrophobic interactions (South et al., 2010). Expression Northern blot analysis from multiple tissues revealed that ASH2L expression is expressed in 14 different tissue types with the highest expression in fetal liver and testes (Lüscher-Firzlaff et al., 2008). ASH2L transcripts were also found to be expressed higher in various Leukemia cell lines, such as K562, Hel, and Dami cells (Lüscher-Firzlaff et al., 2008). Localisation Nucleus. Function Biochemical data has shown that ASH2L is found in a methyltransferase core complex composed of ASH2L, RBBP5, DPY30, WDR5, and the catalytic SET domain containing protein. This core complex is highly conserved and similar to the budding yeast Set1 complex that consists of Set1 (MLL/SET1), Bre2 (ASH2L), Swd1 (RBBP5), Swd3 (WDR5), Swd2 (WDR82), Sdc1 (DPY-30), Spp1 (CFP1/CGBP). ASH2L is also known to associate with numerous additional factors. Many of these additional factors are thought to associate with ASH2L and the H3K4 methyltransferase complexes to target the complex to specific sites within the genome (Cho et al., 2007; Dou et al., 2006; Hughes et al., 2004; Steward et al., 2006; Stoller et al., 2010). Knock-down of ASH2L using siRNA globally decreases H3K4 trimethylation (Dou et al., 2006; Steward et al., 2006). ASH2L and H3K4 methylation both appear to play a key role in oncogenesis (Hess, 2006). ASH2L is found to be over abundant in many cancer cell lines and knock-down of ASH2L by siRNA can prevent tumorigenesis (LüscherFirzlaff et al., 2008). Recent work has suggested that ASH2L in combination with WDR5 and RBBP5 exhibits H3K4 methyltransferase activity (Cao et al., 31 ASH2L (ash2 (absent, small, or homeotic)-like (Drosophila)) South PF, Briggs SD methyltransferase activity by its core components. Nat Struct Mol Biol. 2006 Aug;13(8):713-9. Epub 2006 Jul 30. 2010; Patel et al., 2009; Patel et al., 2011). In addition, this catalytic activity is not dependent on the SET domain containing proteins such as MLL1 (Cao et al., 2010; Patel et al., 2009; Patel et al., 2011). Alternative to ASH2L's function in H3K4 methylation ASH2L may also be playing a role in endosomal trafficking (Xu et al., 2009). ASH2L, DPY-30 and WDR5 were originally implicated in endosomal trafficking when siRNA knock-down of these genes increased the amount of internalized CD8-CIMPR and overexpression increased the amount of cells displaying a altered CIMPR distribution (Xu et al., 2009). Steward MM, Lee JS, O'Donovan A, Wyatt M, Bernstein BE, Shilatifard A.. Molecular regulation of H3K4 trimethylation by ASH2L, a shared subunit of MLL complexes. Nat Struct Mol Biol. 2006 Sep;13(9):852-4. Epub 2006 Aug 6. Woo JS, Imm JH, Min CK, Kim KJ, Cha SS, Oh BH.. Structural and functional insights into the B30.2/SPRY domain. EMBO J. 2006a Mar 22;25(6):1353-63. Epub 2006 Feb 23. Woo JS, Suh HY, Park SY, Oh BH.. Structural basis for protein recognition by B30.2/SPRY domains. Mol Cell. 2006b Dec 28;24(6):967-76. Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, Guszczynski T, Dressler GR, Copeland TD, Kalkum M, Ge K.. PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. J Biol Chem. 2007 Jul 13;282(28):20395-406. Epub 2007 May 11. Homology ASH2L has homologs in eukaryotes from yeast to humans. Simonet T, Dulermo R, Schott S, Palladino F.. Antagonistic functions of SET-2/SET1 and HPL/HP1 proteins in C. elegans development. Dev Biol. 2007 Dec 1;312(1):367-83. Epub 2007 Oct 29. Implicated in Various cancers Note ASH2L mRNA expression does not appear to be misregulated in human cancer cell or primary cell lines. However, expression of ASH2L protein is increased in many cancer cell lines as well as tumor samples (Lüscher-Firzlaff et al., 2008). There was detectable increased staining in the nucleus of ASH2L protein in a wide array of tumors including squamous cell carcinoma of the larynx and the cervix, melanomas, adenocarcinoma of the pancreas, and acinar and ductal breast cancers (Lüscher-Firzlaff et al., 2008). ASH2L protein appears to be more stable in cancer cell lines compared to the normal cell line counterparts and knockdown of ASH2L can prevent tumerogenesis suggesting a role in tumor cell proliferation (LüscherFirzlaff et al., 2008). Champagne KS, Saksouk N, Pena PV, Johnson K, Ullah M, Yang XJ, Cote J, Kutateladze TG.. The crystal structure of the ING5 PHD finger in complex with an H3K4me3 histone peptide. Proteins. 2008 Sep;72(4):1371-6. References Kuang Z, Yao S, Xu Y, Lewis RS, Low A, Masters SL, Willson TA, Kolesnik TB, Nicholson SE, Garrett TJ, Norton RS.. SPRY domain-containing SOCS box protein 2: crystal structure and residues critical for protein binding. J Mol Biol. 2009 Feb 27;386(3):662-74. Epub 2009 Jan 6. Luscher-Firzlaff J, Gawlista I, Vervoorts J, Kapelle K, Braunschweig T, Walsemann G, Rodgarkia-Schamberger C, Schuchlautz H, Dreschers S, Kremmer E, Lilischkis R, Cerni C, Wellmann A, Luscher B.. The human trithorax protein hASH2 functions as an oncoprotein. Cancer Res. 2008 Feb 1;68(3):749-58. van Ingen H, van Schaik FM, Wienk H, Ballering J, Rehmann H, Dechesne AC, Kruijzer JA, Liskamp RM, Timmers HT, Boelens R.. Structural insight into the recognition of the H3K4me3 mark by the TFIID subunit TAF3. Structure. 2008 Aug 6;16(8):1245-56. Champagne KS, Kutateladze TG.. Structural insight into histone recognition by the ING PHD fingers. Curr Drug Targets. 2009 May;10(5):432-41. (REVIEW) Roguev A, Schaft D, Shevchenko A, Pijnappel WW, Wilm M, Aasland R, Stewart AF. The Saccharomyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone 3 lysine 4. EMBO J. 2001 Dec 17;20(24):7137-48 Patel A, Dharmarajan V, Vought VE, Cosgrove MS.. On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. 2009 Sep 4;284(36):24242-56. Epub 2009 Jun 25. Wang J, Zhou Y, Yin B, Du G, Huang X, Li G, Shen Y, Yuan J, Qiang B. ASH2L: alternative splicing and downregulation during induced megakaryocytic differentiation of multipotential leukemia cell lines. J Mol Med (Berl). 2001 Jul;79(7):399-405 Xu Z, Gong Q, Xia B, Groves B, Zimmermann M, Mugler C, Mu D, Matsumoto B, Seaman M, Ma D.. A role of histone H3 lysine 4 methyltransferase components in endosomal trafficking. J Cell Biol. 2009 Aug 10;186(3):343-53. Epub 2009 Aug 3. Hess JL.. MLL: Deep Insight. Atlas Genet Cytogenet Oncol Haematol. August 2003 . Hughes CM, Rozenblatt-Rosen O, Milne TA, Copeland TD, Levine SS, Lee JC, Hayes DN, Shanmugam KS, Bhattacharjee A, Biondi CA, Kay GF, Hayward NK, Hess JL, Meyerson M.. Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell. 2004 Feb 27;13(4):587-97. Cao F, Chen Y, Cierpicki T, Liu Y, Basrur V, Lei M, Dou Y.. An Ash2L/RbBP5 heterodimer stimulates the MLL1 methyltransferase activity through coordinated substrate interactions with the MLL1 SET domain. PLoS One. 2010 Nov 23;5(11):e14102. Rhodes DA, de Bono B, Trowsdale J.. Relationship between SPRY and B30.2 protein domains. Evolution of a component of immune defence? Immunology. 2005 Dec;116(4):411-7. (REVIEW) Filippakopoulos P, Low A, Sharpe TD, Uppenberg J, Yao S, Kuang Z, Savitsky P, Lewis RS, Nicholson SE, Norton RS, Bullock AN.. Structural basis for Par-4 recognition by the SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, and SPSB4. J Mol Biol. 2010 Aug 20;401(3):389-402. Epub 2010 Jun 16. Dou Y, Milne TA, Ruthenburg AJ, Lee S, Lee JW, Verdine GL, Allis CD, Roeder RG.. Regulation of MLL1 H3K4 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 32 ASH2L (ash2 (absent, small, or homeotic)-like (Drosophila)) South PF, Briggs SD South PF, Fingerman IM, Mersman DP, Du HN, Briggs SD.. A conserved interaction between the SDI domain of Bre2 and the Dpy-30 domain of Sdc1 is required for histone methylation and gene expression. J Biol Chem. 2010 Jan 1;285(1):595-607. Epub 2009 Nov 6. Patel A, Vought VE, Dharmarajan V, Cosgrove MS.. A novel non-SET domain multi-subunit methyltransferase required for sequential nucleosomal histone H3 methylation by the mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. 2011 Feb 4;286(5):3359-69. Epub 2010 Nov 24. Stoller JZ, Huang L, Tan CC, Huang F, Zhou DD, Yang J, Gelb BD, Epstein JA.. Ash2l interacts with Tbx1 and is required during early embryogenesis. Exp Biol Med (Maywood). 2010 May;235(5):569-76. Sarvan S, Avdic V, Tremblay V, Chaturvedi CP, Zhang P, Lanouette S, Blais A, Brunzelle JS, Brand M, Couture JF.. Crystal structure of the trithorax group protein ASH2L reveals a forkhead-like DNA binding domain. Nat Struct Mol Biol. 2011 Jun 5;18(7):857-9. doi: 10.1038/nsmb.2093. Avdic V, Zhang P, Lanouette S, Groulx A, Tremblay V, Brunzelle J, Couture JF.. Structural and biochemical insights into MLL1 core complex assembly. Structure. 2011 Jan 12;19(1):101-8. This article should be referenced as such: South PF, Briggs SD. ASH2L (ash2 (absent, small, or homeotic)-like (Drosophila)). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):30-33. Chen Y, Wan B, Wang KC, Cao F, Yang Y, Protacio A, Dou Y, Chang HY, Lei M.. Crystal structure of the N-terminal region of human Ash2L shows a winged-helix motif involved in DNA binding. EMBO Rep. 2011 Jun 10;12(8):797-803. doi: 10.1038/embor.2011.101. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 33 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review CD109 (CD109 molecule) Shinji Mii, Yoshiki Murakumo, Masahide Takahashi Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan (SM, YM, MT) Published in Atlas Database: August 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/CD109ID42925ch6q13.html DOI: 10.4267/2042/47266 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Protein Other names: CPAMD7, DKFZp762L1111, FLJ38569, FLJ41966, RP11-525G3.1 HGNC (Hugo): CD109 Location: 6q13 Note CD109 is a glycosylphosphatidylinositol (GPI)anchored cell-surface glycoprotein and is a member of the alpha-2-macroglobulin/C3,C4,C5 family of thioester-containing proteins. Description CD109 is a GPI-anchored cell-surface glycoprotein and is a member of the alpha-2-macroglobulin/C3,C4,C5 family of thioester-containing proteins (Sutherland et al., 1991; Haregewoin et al., 1994; Smith et al., 1995; Lin et al., 2002). The CD109 protein was first identified as a cell-surface antigen detected by a monoclonal antibody raised against the primitive lymphoid/myeloid cell line KG1a (Sutherland et al., 1991). It was also shown that CD109 carries the biallelic platelet-specific alloantigen Gov (Kelton et al., 1990; Smith et al., 1995). DNA/RNA Description Expression CD109 is a gene of 132.53 kb comprising 33 exons and 32 introns. The 5' part of exon 1 and the 3' part of exon 33 are non-coding. CD109 is expressed on a subset of fetal and adult CD34+ bone marrow mononuclear cells, mesenchymal stem cell subsets, phytohemagglutinin (PHA)-activated T lymphoblasts, thrombin-activated platelets, leukemic megakaryoblasts, endothelial cells, and some human tumor cell lines, but not on fresh peripheral leukocytes and normal bone marrow leukocytes (Kelton et al., 1990; Murray et al., 1999; Giesert et al., 2003). Transcription Three splice variants are known. The length of the longest variant is 9464 bp (CDS: 426-4763). mRNA is mainly expressed in skin and testis. Pseudogene Not known. Exon-intron structure of CD109 gene. The vertical bars correspond to exons. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 34 CD109 (CD109 molecule) Mii S, et al. Representation of the CD109 protein with localization of recognized domains. CD109 protein is a GPI-anchored protein having signal peptide, Gov antigen, thioester region, and furinase cleavage site. In normal human tissues other than hematopoietic cells, CD109 is expressed in limited cells including the myoepithelial cells of the mammary, lacrimal, salivary and bronchial glands and the basal cells of the prostate and the bronchial epithelia (Hashimoto et al., 2004; Zhang et al., 2005; Sato et al., 2007; Hasegawa et al., 2007; Hasegawa et al., 2008). Recently, it has been reported that CD109 is highly expressed in several types of human cancer tissues, in particular squamous cell carcinomas (Hashimoto et al., 2004; Zhang et al., 2005; Sato et al., 2007; Hasegawa et al., 2007; Hasegawa et al., 2008; Järvinen et al., 2008; Hagiwara et al., 2008; Ohshima et al., 2010; Hagikura et al., 2010). urothelial carcinomas of the urinary bladder than in moderately- or poorly-differentiated SCCs and in highgrade urothelial carcinomas, respectively (Hagiwara et al., 2008; Hagikura et al., 2010). Alloimmune thrombocytopenic syndromes Plasma membrane. Note Refractoriness to platelet transfusion, post-transfusion purpura, and neonatal alloimmune thrombocytopenia (Smith et al., 1995). Disease These diseases are included in alloimmune platelet thrombocytopenic syndromes. Gova/b alloantigens, which reside in the CD109 protein, are the cause of these 3 diseases. Function References CD109 negatively regulates TGF-beta signaling in keratinocytes by directly modulating TGF-beta receptor activity in vitro (Finnson et al., 2006). Kelton JG, Smith JW, Horsewood P, Humbert JR, Hayward CP, Warkentin TE. Gova/b alloantigen system on human platelets. Blood. 1990 Jun 1;75(11):2172-6 Localisation Homology Sutherland DR, Yeo E, Ryan A, Mills GB, Bailey D, Baker MA. Identification of a cell-surface antigen associated with activated T lymphoblasts and activated platelets. Blood. 1991 Jan 1;77(1):84-93 Orthologs: mouse CD109, rat CD109, cow CD109, dog CD109, chicken CD109, hagfish CD109, nematode CD109. Paralogs: alpha-2-macroglobulin, alpha-2macroglobulin-like-1, C3, C4, C5, PZP, CPAMD8. Haregewoin A, Solomon K, Hom RC, Soman G, Bergelson JM, Bhan AK, Finberg RW. Cellular expression of a GPI-linked T cell activation protein. Cell Immunol. 1994 Jul;156(2):357-70 Smith JW, Hayward CP, Horsewood P, Warkentin TE, Denomme GA, Kelton JG. Characterization and localization of the Gova/b alloantigens to the glycosylphosphatidylinositolanchored protein CDw109 on human platelets. Blood. 1995 Oct 1;86(7):2807-14 Mutations Note A Tyr703Ser polymorphism of CD109 is associated with Gova and Govb alloantigenic determination (Schuh et al., 2002). Murray LJ, Bruno E, Uchida N, Hoffman R, Nayar R, Yeo EL, Schuh AC, Sutherland DR. CD109 is expressed on a subpopulation of CD34+ cells enriched in hematopoietic stem and progenitor cells. Exp Hematol. 1999 Aug;27(8):1282-94 Implicated in Lin M, Sutherland DR, Horsfall W, Totty N, Yeo E, Nayar R, Wu XF, Schuh AC. Cell surface antigen CD109 is a novel member of the alpha(2) macroglobulin/C3, C4, C5 family of thioester-containing proteins. Blood. 2002 Mar 1;99(5):1683-91 Various cancer Note CD109 is upregulated in squamous cell carcinomas (SCCs) of lung, esophagus, uterus and oral cavity, malignant melanoma of skin, and urothelial carcinoma of urinary bladder (Hashimoto et al., 2004; Zhang et al., 2005; Sato et al., 2007; Hasegawa et al., 2007; Hasegawa et al., 2008; Järvinen et al., 2008; Hagiwara et al., 2008; Ohshima et al., 2010; Hagikura et al., 2010). Prognosis The CD109 expression is significantly higher in welldifferentiated SCCs of the oral cavity and in low-grade Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Schuh AC, Watkins NA, Nguyen Q, Harmer NJ, Lin M, Prosper JY, Campbell K, Sutherland DR, Metcalfe P, Horsfall W, Ouwehand WH. A tyrosine703serine polymorphism of CD109 defines the Gov platelet alloantigens. Blood. 2002 Mar 1;99(5):1692-8 Giesert C, Marxer A, Sutherland DR, Schuh AC, Kanz L, Buhring HJ. Antibody W7C5 defines a CD109 epitope expressed on CD34+ and CD34- hematopoietic and mesenchymal stem cell subsets. Ann N Y Acad Sci. 2003 May;996:227-30 Hashimoto M, Ichihara M, Watanabe T, Kawai K, Koshikawa K, Yuasa N, Takahashi T, Yatabe Y, Murakumo Y, Zhang JM, 35 CD109 (CD109 molecule) Mii S, et al. Nimura Y, Takahashi M. Expression of CD109 in human cancer. Oncogene. 2004 Apr 29;23(20):3716-20 Hagiwara S, Murakumo Y, Sato T, Shigetomi T, Mitsudo K, Tohnai I, Ueda M, Takahashi M. Up-regulation of CD109 expression is associated with carcinogenesis of the squamous epithelium of the oral cavity. Cancer Sci. 2008 Oct;99(10):1916-23 Zhang JM, Hashimoto M, Kawai K, Murakumo Y, Sato T, Ichihara M, Nakamura S, Takahashi M. CD109 expression in squamous cell carcinoma of the uterine cervix. Pathol Int. 2005 Apr;55(4):165-9 Järvinen AK, Autio R, Kilpinen S, Saarela M, Leivo I, Grénman R, Mäkitie AA, Monni O. High-resolution copy number and gene expression microarray analyses of head and neck squamous cell carcinoma cell lines of tongue and larynx. Genes Chromosomes Cancer. 2008 Jun;47(6):500-9 Finnson KW, Tam BY, Liu K, Marcoux A, Lepage P, Roy S, Bizet AA, Philip A. Identification of CD109 as part of the TGFbeta receptor system in human keratinocytes. FASEB J. 2006 Jul;20(9):1525-7 Hagikura M, Murakumo Y, Hasegawa M, Jijiwa M, Hagiwara S, Mii S, Hagikura S, Matsukawa Y, Yoshino Y, Hattori R, Wakai K, Nakamura S, Gotoh M, Takahashi M. Correlation of pathological grade and tumor stage of urothelial carcinomas with CD109 expression. Pathol Int. 2010 Nov;60(11):735-43 Hasegawa M, Hagiwara S, Sato T, Jijiwa M, Murakumo Y, Maeda M, Moritani S, Ichihara S, Takahashi M. CD109, a new marker for myoepithelial cells of mammary, salivary, and lacrimal glands and prostate basal cells. Pathol Int. 2007 May;57(5):245-50 Ohshima Y, Yajima I, Kumasaka MY, Yanagishita T, Watanabe D, Takahashi M, Inoue Y, Ihn H, Matsumoto Y, Kato M. CD109 expression levels in malignant melanoma. J Dermatol Sci. 2010 Feb;57(2):140-2 Sato T, Murakumo Y, Hagiwara S, Jijiwa M, Suzuki C, Yatabe Y, Takahashi M. High-level expression of CD109 is frequently detected in lung squamous cell carcinomas. Pathol Int. 2007 Nov;57(11):719-24 This article should be referenced as such: Hasegawa M, Moritani S, Murakumo Y, Sato T, Hagiwara S, Suzuki C, Mii S, Jijiwa M, Enomoto A, Asai N, Ichihara S, Takahashi M. CD109 expression in basal-like breast carcinoma. Pathol Int. 2008 May;58(5):288-94 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Mii S, Murakumo Y, Takahashi M. CD109 (CD109 molecule). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):34-36. 36 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review CLDN7 (claudin 7) Ana Carolina de Carvalho, Andre Vettore Laboratory of Cancer Molecular Biology, Department of Biological Sciences, Federal University of Sao Paulo, Diadema, SP, Brazil (ACd, AV) Published in Atlas Database: August 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/CLDN7ID40099ch17p13.html DOI: 10.4267/2042/47267 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Transcription Identity Other names: CEPTRL2, Hs.84359, claudin-1 HGNC (Hugo): CLDN7 Location: 17p13.1 CLDN-7, This gene contains 4 exons and 3 introns. The transcription produces 3 alternatively spliced mRNA variants: - variant 1 (NM_001307.5) encodes the longer isoform; - variant 2 (NM_001185022.1) has an alternate 5' UTR sequence; - variant 3 (NM_001185023.1) lacks an exon in the 3' CDS. CPETRL2, DNA/RNA Description Pseudogene 2573 base-pairs, starts at 7163223 and ends at 7165795 bp from pter with minus strand orientation. The sequence named LOC100129851 claudin 7 pseudogene is a pseudogene of Claudin 7 located at Xp11.4. Figure 1. Schematic representation of the claudin 7 chromosome location, transcript variants and protein isoforms. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 37 CLDN7 (claudin 7) de Carvalho AC, Vettore A Figure 2. Schematic representation of the claudin 7 protein showing the extracellular loops (EL1 and EL2), the transmembrane domains (TM1 to TM4) and its amino- and carboxy-terminal tails extending into the cytoplasm. VATMGMKCTRCGGDDKVKKARIAMGGGIIFIVA GMSLALPSLLAGQGLP Protein Description CLDN-7 is an integral membrane protein with four hydrophobic transmembrane domains and two extracellular loops which appear to be implicated in tight junction formation and with their amino- and carboxy-terminal tails extending into the cytoplasm (figure 2). The transcription of this gene gives 3 alternatively spliced mRNA variants that encode 2 different protein isoforms (variants 1 and 2 encode the same isoform): - Isoform 1 is the canonical sequence with 211 amino acids and it weighs 22418 Da. MANSGLQLLGFSMALLGWVGLVACTAIPQWQM SSYAGDNIITAQAMYKGLWMDCVTQSTGMMSC KMYDSVLALSAALQATRALMVVSLVLGFLAMF VATMGMKCTRCGGDDKVKKARIAMGGGIIFIVA GLAALVACSWYGHQIVTDFYNPLIPTNIKYEFGP AIFIGWAGSALVILGGALLSCSCPGNESKAGYRV PRSYPKSNSSKEYV Localisation The protein is localized in the cell membrane as a constituent of tight junctions. Function CLDN-7 encodes a member of the claudin family of integral transmembrane proteins that are components of tight junction strands. Claudins regulate the paracellular transport being essential in maintaining a functional epithelial barrier, and also play critical roles in maintaining cell polarity and signal transductions. Studies have shown that altered levels of the different claudins may be related to invasion and progression of carcinoma cells in several primary neoplasms. - Isoform 2 contains 145 amino acids, with a shorter Cterminus, lacking amino acids 159 to 211 in comparison to isoform 1. It weighs 15156 Da. MANSGLQLLGFSMALLGWVGLVACTAIPQWQM SSYAGDNIITAQAMYKGLWMDCVTQSTGMMSC KMYDSVLALSAALQATRALMVVSLVLGFLAMF Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 38 CLDN7 (claudin 7) de Carvalho AC, Vettore A Esophageal cancer Mutations Prognosis Usami et al. (2006) found that reduced expression of Claudin 7 at the invasive front of the esophageal cancer was significantly associated with the depth of invasion, lymphatic vessel invasion, and lymph node metastasis. Reduced Claudin 7 expression was also found in the metastatic lymph nodes. They suggest that the reduced expression of Claudin 7 at the invasive front of esophageal squamous cell carcinoma may lead to tumor progression and subsequent metastatic events. Somatic In the catalogue of Somatic Mutations in Cancer (Sanger) reports only a heterozygous silent substitution (339G/T; V113V) in ovarian serous cystadenocarcinoma is present. Polymorphisms According to the Ensembl database 12 variations could be present in the transcripts (variants 1/2) of CLDN-7: Position 963/396 of mRNA a synonymous G/A polymorphism at position 61 of the amino acid sequence. Position 979/412 of mRNA a non-synonymous G/T polymorphism at position 77 of the amino acid sequence. Switching an Ala for an Asp residue. SIFT deleterious. Position 1299/732 of mRNA a non-synonymous C/T polymorphism at position 397 of the amino acid sequence. Switching an Ala for an Thr residue. SIFT tolerated. Position 1425/858 of mRNA a non-synonymous C/A polymorphism at position 523 of the amino acid sequence. Switching an Val for an Phe residue. SIFT deleterious. Position 1492/925 of mRNA a non-synonymous A/G polymorphism at position 590 of the amino acid sequence. Switching an Val for an Ala residue. SIFT tolerated. Position 1508/941 of mRNA a synonymous A/C polymorphism at position 606 of the amino acid sequence. Epithelial ovarian carcinoma Prognosis Kim et al. (2011) described the up-regulation of Claudin 7 transcripts in patients with epithelial ovarian carcinoma (EOCs) in comparison to normal ovarian tissues. The protein Claudin 7 was observed in the majority of the EOCs but not in normal ovarian tissues. High Claudin 7 expression in primary tumor correlated with shorter progression-free survival and poor sensitivity to platinum-based chemotherapy. Claudin 7 inhibition in 2774 and HeyA8 human ovarian cancer cells by siRNA significantly enhanced the sensitivity of these cells to cisplatin treatment. These findings suggest Claudin 7 expression as an independent prognostic factor for progression-free survival in EOCs patients and that it may play a role in regulating response to platinum-based chemotherapy in the treatment of these tumors. Oncogenesis Tassi et al. (2008) found Claudin 7 transcript and protein significantly overexpressed in both primary and metastatic EOCs compared to normal ovaries. Moreover, a strong immunoreactivity for Claudin 7 was detected in EOC cells present in ascites fluids, whereas ascites-derived inflammatory cells, histiocytes, and reactive mesothelial cells were negative. Claudin 7 is significantly overexpressed in all main histologic types of EOC and in single neoplastic cells disseminated in peritoneal cavity and pleural effusions, suggesting its potential role as novel diagnostic marker in ovarian cancer. Implicated in Colorectal carcinoma Prognosis Oshima et al. (2008) studied surgical specimens of cancer tissue and adjacent normal mucosa from patients with untreated colorectal carcinoma. The reduced expression of Claudin 7 correlated with venous invasion and liver metastasis, thus suggesting that the reduced expression of the Claudin 7 gene may be a useful predictor of liver metastasis in patients with colorectal cancer. Oncogenesis Bornholdt et al. (2011) observed that Claudin 7 gene was downregulated both at mRNA and protein levels in biopsies of colorectal tissue from mild/moderate dysplasia, severe dysplasia and carcinomas when comparing to biopsies from healthy individuals. These results suggest that Claudin 7 downregulation is as an early event in colorectal carcinogenesis, probably contributing to the compromised epithelial barrier in adenomas. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Prostatic carcinoma Prognosis Sheehan et al. (2007) reported the pattern of claudin expression in prostatic adenocarcinomas (PACs) and found that the decreased expression of Claudin 7 was correlated with high tumor grade. Oral squamous cell carcinoma Prognosis Lourenço et al. (2010) showed that Claudin 7 expression was mostly negative or weakly expressed in oral squamous cell carcinoma samples. According their 39 CLDN7 (claudin 7) de Carvalho AC, Vettore A both ductal carcinoma in situ and invasive ductal carcinoma of the breast. Oncogene. 2003 Apr 3;22(13):2021-33 results, the loss of Claudin 7 expression was associated with tumor size, clinical stage and a worse disease-free survival. Lee JW, Lee SJ, Seo J, Song SY, Ahn G, Park CS, Lee JH, Kim BG, Bae DS. Increased expressions of claudin-1 and claudin-7 during the progression of cervical neoplasia. Gynecol Oncol. 2005 Apr;97(1):53-9 Uterine cervical neoplasia Oncogenesis Lee et al. (2005) showed that Claudin 7 expressions is associated with the progression of uterine cervical neoplasia since its expression was undetectable in normal cervical squamous epithelium and gradually increase in accordance with the progression from LSIL (low-grade squamous intraepithelial lesion) to HSIL (high-grade squamous intraepithelial lesion) and ISCC (invasive squamous cell carcinoma). Claudin 7 were detected in all cases of ISCC. These authors suggested that Claudin 7 may play a significant role in tumor progression of cervical neoplasia. Sauer T, Pedersen MK, Ebeltoft K, Naess O. Reduced expression of Claudin-7 in fine needle aspirates from breast carcinomas correlate with grading and metastatic disease. Cytopathology. 2005 Aug;16(4):193-8 Usami Y, Chiba H, Nakayama F, Ueda J, Matsuda Y, Sawada N, Komori T, Ito A, Yokozaki H. Reduced expression of claudin-7 correlates with invasion and metastasis in squamous cell carcinoma of the esophagus. Hum Pathol. 2006 May;37(5):569-77 Sheehan GM, Kallakury BV, Sheehan CE, Fisher HA, Kaufman RP Jr, Ross JS. Loss of claudins-1 and -7 and expression of claudins-3 and -4 correlate with prognostic variables in prostatic adenocarcinomas. Hum Pathol. 2007 Apr;38(4):564-9 Breast cancer Oshima T, Kunisaki C, Yoshihara K, Yamada R, Yamamoto N, Sato T, Makino H, Yamagishi S, Nagano Y, Fujii S, Shiozawa M, Akaike M, Wada N, Rino Y, Masuda M, Tanaka K, Imada T. Reduced expression of the claudin-7 gene correlates with venous invasion and liver metastasis in colorectal cancer. Oncol Rep. 2008 Apr;19(4):953-9 Prognosis Kominsky et al. (2003) conducted RT-PCR and Western Blot analysis and reported that Claudin 7 expression is lower in breast invasive ductal carcinomas (IDC) than in normal breast epithelium. They also reported immunohistochemical (IHC) analysis of ductal carcinoma in situ (DCIS) and IDC and showed that the loss of Claudin 7 expression is correlated with histological grade, occurring predominantly in high-grade lesions. According to their results, Claudin 7 expression was lost in the vast majority of in situ lobular carcinoma cases. In summary, this study provides insight into the potential role of Claudin 7 in the breast tumor progression and in the ability of breast cancer cells to disseminate. Sauer et al. (2005) evaluated the immunocytochemical expression of Claudin 7 in fine needle aspirates of breast carcinomas and found that reduced Claudin 7 expression was correlated with grading, locoregional and distant metastases, nodal involvement and cellular cohesion in invasive carcinomas. Tassi RA, Bignotti E, Falchetti M, Ravanini M, Calza S, Ravaggi A, Bandiera E, Facchetti F, Pecorelli S, Santin AD. Claudin-7 expression in human epithelial ovarian cancer. Int J Gynecol Cancer. 2008 Nov-Dec;18(6):1262-71 Lourenço SV, Coutinho-Camillo CM, Buim ME, de Carvalho AC, Lessa RC, Pereira CM, Vettore AL, Carvalho AL, Fregnani JH, Kowalski LP, Soares FA. Claudin-7 down-regulation is an important feature in oral squamous cell carcinoma. Histopathology. 2010 Nov;57(5):689-98 Bornholdt J, Friis S, Godiksen S, Poulsen SS, Santoni-Rugiu E, Bisgaard HC, Lothe IM, Ikdahl T, Tveit KM, Johnson E, Kure EH, Vogel LK. The level of claudin-7 is reduced as an early event in colorectal carcinogenesis. BMC Cancer. 2011 Feb 10;11:65 Kim CJ, Lee JW, Choi JJ, Choi HY, Park YA, Jeon HK, Sung CO, Song SY, Lee YY, Choi CH, Kim TJ, Lee JH, Kim BG, Bae DS. High claudin-7 expression is associated with a poor response to platinum-based chemotherapy in epithelial ovarian carcinoma. Eur J Cancer. 2011 Apr;47(6):918-25 References This article should be referenced as such: de Carvalho AC, Vettore A. CLDN7 (claudin 7). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):37-40. Kominsky SL, Argani P, Korz D, Evron E, Raman V, Garrett E, Rein A, Sauter G, Kallioniemi OP, Sukumar S. Loss of the tight junction protein claudin-7 correlates with histological grade in Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 40 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review CSE1L (CSE1 chromosome segregation 1-like (yeast)) Ming-Chung Jiang Division of Hematology and Oncology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan (MCJ) Published in Atlas Database: August 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/CSE1LID40159ch20q13.html DOI: 10.4267/2042/47268 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Description Identity Other names: CAS, CSE1, MGC130036, MGC130037, XPO2 HGNC (Hugo): CSE1L Location: 20q13.13 CSE1L gene encodes a 971-amino acid protein with an approximately 100-kDa molecular mass (Brinkmann et al., 1995). MGC117283, Expression Multiple transcript variants encoding several different isoforms in a tissue-specific manner have been described for CSE1L gene (Brinkmann et al., 1999). CSE1L is expressed in various tissues, and particularly it is highly expressed in most cancer (Tai et al., 2010a; Brinkmann et al., 1995). The expression level CSE1L is positively correlated with high tumor stage, high tumor grade, and worse outcomes of cancer patients (Tai et al., 2010a). The increased expression of CSE1L in cancer is mainly due to the amplification of the copy number of the CSE1L gene in cancer tissue (Tai et al., 2010a). The association of CSE1L with microtubules is related with pseudopodia extension and the migration of cancer cells (Tai et al., 2010b). CSE1L is also a secretory protein, and it is present is the sera of cancer patients. The secretion of CSE1L is related with the invasion of cancer cells (Tung et al., 2009; Stella Tsai et al., 2010). Protein Localisation DNA/RNA Note CDS: 2915 bp. Description The CSE1L gene consists of 25 exons (Brinkmann et al., 1999). The CSE1L gene is high-frequency amplified in various cancer types (Tai et al., 2010a). Transcription Nucleus, cytoplasm. Note CSE1L is a multiple function protein. The protein is involved in nuclear protein transport (Lindsay et al., 2002), cell apoptosis (Brinkmann et al., 1996), microtubule assembly (Scherf et al., 1996), cell secretion (Tsao et al., 2009), and cancer cell invasion (Liao et al., 2008; Tung et al., 2009; Stella Tsai et al., 2010) etc. Function A cell apoptosis susceptibility protein; a microtubuleassociated protein; an export receptor of importin-a in the nuclear protein import cycle; involved in tumor cell invasion and metastasis in cancer progression. Homology The yeast chromosome segregation gene CSE1. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 41 CSE1L (CSE1 chromosome segregation 1-like (yeast)) Jiang MC In contrast, highly malignant non-Hodgkin's lymphoma and malignant cells of Hodgkin's disease displayed very strong CSE1L positivity, with staining of up to 80% of atypical cells (Wellmann et al., 1997). Implicated in Breast cancer Prognosis Benign breast lesions show weak cytoplasmatic CSE1L staining, while in ductal and lobular in situ carcinomas, 70%-90% of breast tumor cells showed heavy CSE1L staining cytoplasm. Also, in invasive ductal and lobular carcinomas, 70-90% of the tumor cells showed heavy CSE1L staining pattern predominantly in nuclei (Behrens et al., 2001). Endometrial carcinomas Prognosis An analysis of 89 endometrial carcinomas and 56 samples of non-neoplastic adjacent endometrium showed that CSE1L was expressed in 93% of endometrial carcinomas neoplastic tissues, while lower levels of CSE1L expression were observed in the adjacent endometrium compared to the carcinomas (p = 0.003). Also, CSE1L expression was higher in grade 3 tumors (p = 0.002) (Peiró et al., 2001). Ovarian carcinoma Prognosis In serous ovarian carcinoma, moderate to strong immunostaining of CSE1L was observed in 34 of 41 cases (83%) of serous carcinomas, and CSE1L immunoreactivity was positively related to the frequency of apoptotic bodies (p = 0.0170), the tumor grade (p = 0.0107), and adverse outcomes (p = 0.0035). CSE1L protein reactivity was present in 100% of 69 ovarian carcinomas, and a significant reciprocal correlation was observed between high levels of CSE1L and the histological type, FIGO (International Federation of Obstetrics and Gynecology) stage III and grade 3, residual tumors of > 2 cm, and 20q13.2 (ZNF217 gene) amplification (> four copies in > 20% cells). A tissue array study composed of 244 serous ovarian tumors of different grades (0-3) and stages (IIV) showed a higher expression of CSE1L in poorly compared to highly differentiated invasive ovarian tumors (Brustmann, 2004; Peiro et al., 2002; Ouellet et al., 2006). Hepatocellular carcinomas Prognosis The expression of CSE1L was not detected in normal hepatocytes, while strong CSE1L expression was detected in hepatocellular carcinoma. Study also showed that the immunohistochemical staining intensity score of CSE1L was significantly higher in human hepatocellular carcinoma than in non-tumor tissue (p < 0.05) (Wellmann et al., 2001; Shiraki et al., 2006). Lung cancer Prognosis The immunophenotypic profiling of non-small cell lung cancer progression using tissue microarray with 59 tissue samples, including 33 primary tumors without distant metastasis and 26 non-small cell lung cancer with brain metastases and showed that elevated expression of CSE1L was significantly associated with the metastatic potential of non-small cell lung cancer (Papay et al., 2007). Melanomas Prognosis Analysis of the expression of CSE1L in 27 control benign and 55 malignant melanocytic lesions (including 32 primary and 23 metastatic lesions), and the results showed that only 13 of the 27 benign melanocytic lesions stained positive for CSE1L. However, 5 of 7 lentigo maligna melanomas, 11 of 12 superficial spreading melanomas, and all acrolentiginous (n = 7) and nodular (n = 6) melanomas showed medium to high intensity immunoreactivity for CSE1L staining. All metastatic melanomas (n = 23) showed strong CSE1L staining. Also, CSE1L detection in clinical stages according to the International Union Against Cancer (UICC) showed an increase from 43% ± 34% CSEL-positive cells in stage I, to 53% ± 26% in stage II, 68% ± 24% in stage III, and 72% ± 24% in stage IV (Böni et al., 1999). Gliomas Prognosis The results of array-based comparative genomic hybridization showed that 57.1% of the glioblastoma multiforme cases had high-frequency amplification of the CSE1L gene. Idbaih et al. investigated a series of 16 low-grade gliomas and their subsequent progression to higher-grade malignancies using a one-megabase bacterial artificial chromosome (BAC)-based array comparative genomic hybridization technique, and reported that the CSE1L gene was associated with the progression of gliomas (Hui et al., 2001; Idbaih et al., 2008). Colorectal carcinoma Prognosis The expression of CSE1L was also reported to be higher in the primary and metastatic human colorectal carcinoma compared to the normal colon mucosa (p < 0.0001). Also, the concentration of CSE1L in serum is positively correlated with the stage of colorectal cancer (Stella Tsai et al., 2010; Seiden-Long et al., 2006). Lymphomas Prognosis In normal lymphoid tissue and malignant lymphomas, low-grade non-Hodgkin's lymphoma revealed weak CSE1L staining, with 10% to 60% of all cells positive. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 42 CSE1L (CSE1 chromosome segregation 1-like (yeast)) Jiang MC References immunohistochemical Jan;92(1):268-76 Brinkmann U, Brinkmann E, Gallo M, Pastan I. Cloning and characterization of a cellular apoptosis susceptibility gene, the human homologue to the yeast chromosome segregation gene CSE1. Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):1042731 Ouellet V, Guyot MC, Le Page C, Filali-Mouhim A, Lussier C, Tonin PN, Provencher DM, Mes-Masson AM. Tissue array analysis of expression microarray candidates identifies markers associated with tumor grade and outcome in serous epithelial ovarian cancer. Int J Cancer. 2006 Aug 1;119(3):599607 Brinkmann U, Brinkmann E, Gallo M, Scherf U, Pastan I. Role of CAS, a human homologue to the yeast chromosome segregation gene CSE1, in toxin and tumor necrosis factor mediated apoptosis. Biochemistry. 1996 May 28;35(21):6891-9 study. Gynecol Oncol. 2004 Seiden-Long IM, Brown KR, Shih W, Wigle DA, Radulovich N, Jurisica I, Tsao MS. Transcriptional targets of hepatocyte growth factor signaling and Ki-ras oncogene activation in colorectal cancer. Oncogene. 2006 Jan 5;25(1):91-102 Scherf U, Pastan I, Willingham MC, Brinkmann U. The human CAS protein which is homologous to the CSE1 yeast chromosome segregation gene product is associated with microtubules and mitotic spindle. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2670-4 Shiraki K, Fujikawa K, Sugimoto K, Ito T, Yamanaka T, Suzuki M, Yoneda K, Sugimoto K, Takase K, Nakano T. Cellular apoptosis susceptibility protein and proliferation in human hepatocellular carcinoma. Int J Mol Med. 2006 Jul;18(1):77-81 Wellmann A, Krenacs L, Fest T, Scherf U, Pastan I, Raffeld M, Brinkmann U. Localization of the cell proliferation and apoptosis-associated CAS protein in lymphoid neoplasms. Am J Pathol. 1997 Jan;150(1):25-30 Papay J, Krenacs T, Moldvay J, Stelkovics E, Furak J, Molnar B, Kopper L. Immunophenotypic profiling of nonsmall cell lung cancer progression using the tissue microarray approach. Appl Immunohistochem Mol Morphol. 2007 Mar;15(1):19-30 Böni R, Wellmann A, Man YG, Hofbauer G, Brinkmann U. Expression of the proliferation and apoptosis-associated CAS protein in benign and malignant cutaneous melanocytic lesions. Am J Dermatopathol. 1999 Apr;21(2):125-8 Idbaih A, Carvalho Silva R, Crinière E, Marie Y, Carpentier C, Boisselier B, Taillibert S, Rousseau A, Mokhtari K, Ducray F, Thillet J, Sanson M, Hoang-Xuan K, Delattre JY. Genomic changes in progression of low-grade gliomas. J Neurooncol. 2008 Nov;90(2):133-40 Brinkmann U, Brinkmann E, Bera TK, Wellmann A, Pastan I. Tissue-specific alternative splicing of the CSE1L/CAS (cellular apoptosis susceptibility) gene. Genomics. 1999 May 15;58(1):41-9 Liao CF, Luo SF, Li LT, Lin CY, Chen YC, Jiang MC. CSE1L/CAS, the cellular apoptosis susceptibility protein, enhances invasion and metastasis but not proliferation of cancer cells. J Exp Clin Cancer Res. 2008 Jul 3;27:15 Behrens P, Brinkmann U, Fogt F, Wernert N, Wellmann A. Implication of the proliferation and apoptosis associated CSE1L/CAS gene for breast cancer development. Anticancer Res. 2001 Jul-Aug;21(4A):2413-7 Tung MC, Tsai CS, Tung JN, Tsao TY, Chen HC, Yeh KT, Liao CF, Jiang MC. Higher prevalence of secretory CSE1L/CAS in sera of patients with metastatic cancer. Cancer Epidemiol Biomarkers Prev. 2009 May;18(5):1570-7 Hui AB, Lo KW, Yin XL, Poon WS, Ng HK. Detection of multiple gene amplifications in glioblastoma multiforme using array-based comparative genomic hybridization. Lab Invest. 2001 May;81(5):717-23 Tsao TY, Tsai CS, Tung JN, Chen SL, Yue CH, Liao CF, Wang CC, Jiang MC. Function of CSE1L/CAS in the secretion of HT29 human colorectal cells and its expression in human colon. Mol Cell Biochem. 2009 Jul;327(1-2):163-70 Peiró G, Diebold J, Baretton GB, Kimmig R, Löhrs U. Cellular apoptosis susceptibility gene expression in endometrial carcinoma: correlation with Bcl-2, Bax, and caspase-3 expression and outcome. Int J Gynecol Pathol. 2001 Oct;20(4):359-67 Stella Tsai CS, Chen HC, Tung JN, Tsou SS, Tsao TY, Liao CF, Chen YC, Yeh CY, Yeh KT, Jiang MC. Serum cellular apoptosis susceptibility protein is a potential prognostic marker for metastatic colorectal cancer. Am J Pathol. 2010 Apr;176(4):1619-28 Wellmann A, Flemming P, Behrens P, Wuppermann K, Lang H, Oldhafer K, Pastan I, Brinkmann U. High expression of the proliferation and apoptosis associated CSE1L/CAS gene in hepatitis and liver neoplasms: correlation with tumor progression. Int J Mol Med. 2001 May;7(5):489-94 Tai CJ, Hsu CH, Shen SC, Lee WR, Jiang MC. Cellular apoptosis susceptibility (CSE1L/CAS) protein in cancer metastasis and chemotherapeutic drug-induced apoptosis. J Exp Clin Cancer Res. 2010a Aug 11;29:110 Lindsay ME, Plafker K, Smith AE, Clurman BE, Macara IG. Npap60/Nup50 is a tri-stable switch that stimulates importinalpha:beta-mediated nuclear protein import. Cell. 2002 Aug 9;110(3):349-60 Tai CJ, Shen SC, Lee WR, Liao CF, Deng WP, Chiou HY, Hsieh CI, Tung JN, Chen CS, Chiou JF, Li LT, Lin CY, Hsu CH, Jiang MC. Increased cellular apoptosis susceptibility (CSE1L/CAS) protein expression promotes protrusion extension and enhances migration of MCF-7 breast cancer cells. Exp Cell Res. 2010b Oct 15;316(17):2969-81 Peiró G, Diebold J, Löhrs U. CAS (cellular apoptosis susceptibility) gene expression in ovarian carcinoma: Correlation with 20q13.2 copy number and cyclin D1, p53, and Rb protein expression. Am J Clin Pathol. 2002 Dec;118(6):9229 This article should be referenced as such: Jiang MC. CSE1L (CSE1 chromosome segregation 1-like (yeast)). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):41-43. Brustmann H. Expression of cellular apoptosis susceptibility protein in serous ovarian carcinoma: a clinicopathologic and Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 43 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5) Zhi-Ren Liu Departments of Biology, Georgia State University, Atlanta, GA 30303, USA (ZRL) Published in Atlas Database: August 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/DDX5ID40290ch17q23.html DOI: 10.4267/2042/47269 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Yang et al., 2006), pre-rRNA processing (Jalal et al., 2007), pre-miRNA processing (Fukuda et al., 2007), DNA methylation and de-methylation (Jost et al., 1999), and chromatin remodeling (Carter et al., 2010). A number of different post-translational modifications of p68 are reported, including phosphorylations, sumoylation, and ubiquitylation (Causevic et al., 2001; Yang et al., 2005; Jacobs et al., 2007). Identity Other names: DKFZp434E109, DKFZp686J01190, G17P1, HLR1, HUMP68, p68 HGNC (Hugo): DDX5 Location: 17q23.3 Note DDX5/p68 RNA helicase is a member of DEAD box RNA helicases. As an example of a cellular RNA helicase, the ATPase and the RNA unwinding activities of p68 RNA helicase were documented with the protein that was purified from human 293 cells (Iggo and Lane, 1989; Ford et al.,1988; Hirling et al., 1989) and recombinant protein expressed in E. coli (Huang and Liu, 2002). The gene is expressed in all dividing cells of different vertebrates (Lane and Hoeffler, 1980; Stevenson et al., 1998). p68 RNA helicase is involved in multiple cellular processes, including gene transcription (Endoh et al., 1999; Rossow and Janknecht, 2003), pre-mRNA processing (Liu, 2002; DNA/RNA Note DDX5/p68 RNA helicase is expressed in dividing cells of different vertebrates. Transcription of p68 RNA helicase gene generates a single mRNA precusor with 13 exons and 12 introns. Alternative splicing produces two mRNA transcripts, 2.3 kb and 4.4 kb (Rössler et al., 2000). The 2.3 kb mRNA transcript codes full length p68, while no translational product from the 4.4 kb mRNA transcript is detected in cellular and tissue extracts (Rössler et al., 2000). Diagram of pre-mRNA of p68 RNA helicase. The red bars are exons and the blue thin lines are introns. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 44 DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5) Liu ZR Domain structure of p68 RNA helicase. Functional sequence motifs are marked. Epithelial-Mesenchymal-Transition (EMT).p68 becomes phosphorylated at Y593 upon growth factor stimulation by c-Abl. The tyrosine phosphorylation of p68 mediates growth factor stimulated EpithelialMesenchymal-Transition (EMT) (Yang et al., 2006). Other functions. (1) p68 RNA helicase is shown to unwind the human let-7 microRNA precursor duplex. The protein is required for let-7-directed silencing of gene expression (Salzman et al., 2007). p68 is an indispensible part of Drosha complex. Its activity is required for primary miRNA and rRNA processing (Fukuda et al., 2007). (2) It is also demonstrated that the RNA helicases p68/p72 and the noncoding RNA SRA are coregulators of MyoD and skeletal muscle differentiation (Caretti et al., 2006). (3) Phosphorylation of p68 at Thr residues mediates cell apoptosis (Yang et al., 2007). Protein Description Size of p68; 614 amino acids, 69 kDa. Expression Expressed in almost all tissue types. Its expression is increased in cancer cells. Localisation Dominately localized in the cell nucleus. It is also found in the cytoplasm in various physiological conditions. p68 is a nucleocytoplasm shuttling protein (Wang et al., 2009). Function Pre-mRNA splicing.The protein was demonstrated to associate with spliceosome by mass-spectroscopy and an RNA-protein crosslinking analyses (Hartmuth et al., 2002; Liu et al., 1997; Neubauer et al., 1998). p68 is functionally involved in assemble of the splicesome by mediating the U1 snRNP and the 5'ss interaction (Liu, 2002). p68 RNA helicase is also shown to regulate the splice site selection in the alternative splicing of several growth related genes, such as c-H-ras and tau (Kar et al., 2011; Guil et al., 2003). Transcriptional regulation.The protein is shown to involve in transcriptional regulation by different mechanism of actions dependent on each individual regulated gene and biological processes (Stevenson et al., 1998; Endoh et al., 1999; Yang et al., 2005; Kahlina et al., 2004; Wei and Hu, 2001; Warner et al., 2004). p68 may regulate gene transcription by direct interaction with transcription factors or activators, such as p53, ERalpha (Endoh et al., 1999; Bates et al., 2005), or by mediating chromatin remodeling, such as modulating chromatin remodeling complex (Carter et al., 2010). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Homology Yeast DBP2. Mutations Note Very few mutations of p68 gene were reported. A recent study shows that a S480A mutation in hepatic stellate cells is associated with hepatic fibrosis (Guo et al., 2010). Implicated in Colon cancer Note p68 expression is significantly increased in colon cancer (Shin et al., 2007). Phosphorylation of p68 at Tyr correlation with colon cancer metastasis (Yang et al., 2006; Yang et al., 2005). 45 DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5) Liu ZR ras alternative splicing regulation. Mol Cell Biol. 2003 Apr;23(8):2927-41 Prognosis Phosphorylation of p68 at tyrosine can be used as a diagnosis/prognosis marker for cancer. Rossow KL, Janknecht R. Synergism between p68 RNA helicase and the transcriptional coactivators CBP and p300. Oncogene. 2003 Jan 9;22(1):151-6 References Kahlina K, Goren I, Pfeilschifter J, Frank S. p68 DEAD box RNA helicase expression in keratinocytes. Regulation, nucleolar localization, and functional connection to proliferation and vascular endothelial growth factor gene expression. J Biol Chem. 2004 Oct 22;279(43):44872-82 Lane DP, Hoeffler WK. SV40 large T shares an antigenic determinant with a cellular protein of molecular weight 68,000. Nature. 1980 Nov 13;288(5787):167-70 Ford MJ, Anton IA, Lane DP. Nuclear protein with sequence homology to translation initiation factor eIF-4A. Nature. 1988 Apr 21;332(6166):736-8 Warner DR, Bhattacherjee V, Yin X, Singh S, Mukhopadhyay P, Pisano MM, Greene RM. Functional interaction between Smad, CREB binding protein, and p68 RNA helicase. Biochem Biophys Res Commun. 2004 Nov 5;324(1):70-6 Hirling H, Scheffner M, Restle T, Stahl H. RNA helicase activity associated with the human p68 protein. Nature. 1989 Jun 15;339(6225):562-4 Bates GJ, Nicol SM, Wilson BJ, Jacobs AM, Bourdon JC, Wardrop J, Gregory DJ, Lane DP, Perkins ND, Fuller-Pace FV. The DEAD box protein p68: a novel transcriptional coactivator of the p53 tumour suppressor. EMBO J. 2005 Feb 9;24(3):54353 Iggo RD, Lane DP. Nuclear protein p68 is an RNA-dependent ATPase. EMBO J. 1989 Jun;8(6):1827-31 Liu ZR, Laggerbauer B, Lührmann R, Smith CW. Crosslinking of the U5 snRNP-specific 116-kDa protein to RNA hairpins that block step 2 of splicing. RNA. 1997 Nov;3(11):1207-19 Yang L, Lin C, Liu ZR. Phosphorylations of DEAD box p68 RNA helicase are associated with cancer development and cell proliferation. Mol Cancer Res. 2005 Jun;3(6):355-63 Neubauer G, King A, Rappsilber J, Calvio C, Watson M, Ajuh P, Sleeman J, Lamond A, Mann M. Mass spectrometry and EST-database searching allows characterization of the multiprotein spliceosome complex. Nat Genet. 1998 Sep;20(1):4650 Stevenson RJ, Hamilton SJ, MacCallum DE, Pace FV. Expression of the 'dead box' RNA developmentally and growth regulated and organ differentiation/maturation in the fetus. Apr;184(4):351-9 Caretti G, Schiltz RL, Dilworth FJ, Di Padova M, Zhao P, Ogryzko V, Fuller-Pace FV, Hoffman EP, Tapscott SJ, Sartorelli V. The RNA helicases p68/p72 and the noncoding RNA SRA are coregulators of MyoD and skeletal muscle differentiation. Dev Cell. 2006 Oct;11(4):547-60 Hall PA, Fullerhelicase p68 is correlates with J Pathol. 1998 Yang L, Lin C, Liu ZR. P68 RNA helicase mediates PDGFinduced epithelial mesenchymal transition by displacing Axin from beta-catenin. Cell. 2006 Oct 6;127(1):139-55 Fukuda T, Yamagata K, Fujiyama S, Matsumoto T, Koshida I, Yoshimura K, Mihara M, Naitou M, Endoh H, Nakamura T, Akimoto C, Yamamoto Y, Katagiri T, Foulds C, Takezawa S, Kitagawa H, Takeyama K, O'Malley BW, Kato S. DEAD-box RNA helicase subunits of the Drosha complex are required for processing of rRNA and a subset of microRNAs. Nat Cell Biol. 2007 May;9(5):604-11 Endoh H, Maruyama K, Masuhiro Y, Kobayashi Y, Goto M, Tai H, Yanagisawa J, Metzger D, Hashimoto S, Kato S. Purification and identification of p68 RNA helicase acting as a transcriptional coactivator specific for the activation function 1 of human estrogen receptor alpha. Mol Cell Biol. 1999 Aug;19(8):5363-72 Jost JP, Schwarz S, Hess D, Angliker H, Fuller-Pace FV, Stahl H, Thiry S, Siegmann M. A chicken embryo protein related to the mammalian DEAD box protein p68 is tightly associated with the highly purified protein-RNA complex of 5-MeC-DNA glycosylase. Nucleic Acids Res. 1999 Aug 15;27(16):3245-52 Jacobs AM, Nicol SM, Hislop RG, Jaffray EG, Hay RT, FullerPace FV.. SUMO modification of the DEAD box protein p68 modulates its transcriptional activity and promotes its interaction with HDAC1. Oncogene. 2007 Aug 30;26(40):586676. Epub 2007 Mar 19. Rössler OG, Hloch P, Schütz N, Weitzenegger T, Stahl H. Structure and expression of the human p68 RNA helicase gene. Nucleic Acids Res. 2000 Feb 15;28(4):932-9 Jalal C, Uhlmann-Schiffler H, Stahl H.. Redundant role of DEAD box proteins p68 (Ddx5) and p72/p82 (Ddx17) in ribosome biogenesis and cell proliferation. Nucleic Acids Res. 2007;35(11):3590-601. Epub 2007 May 7. Causevic M, Hislop RG, Kernohan NM, Carey FA, Kay RA, Steele RJ, Fuller-Pace FV. Overexpression and polyubiquitylation of the DEAD-box RNA helicase p68 in colorectal tumours. Oncogene. 2001 Nov 22;20(53):7734-43 Salzman DW, Shubert-Coleman J, Furneaux H.. P68 RNA helicase unwinds the human let-7 microRNA precursor duplex and is required for let-7-directed silencing of gene expression. J Biol Chem. 2007 Nov 9;282(45):32773-9. Epub 2007 Aug 27. Wei Y, Hu MH. [The study of P68 RNA helicase on cell transformation]. Yi Chuan Xue Bao. 2001 Nov;28(11):991-6 Shin S, Rossow KL, Grande JP, Janknecht R.. Involvement of RNA helicases p68 and p72 in colon cancer. Cancer Res. 2007 Aug 15;67(16):7572-8. Hartmuth K, Urlaub H, Vornlocher HP, Will CL, Gentzel M, Wilm M, Lührmann R. Protein composition of human prespliceosomes isolated by a tobramycin affinity-selection method. Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):1671924 Yang L, Lin C, Sun SY, Zhao S, Liu ZR.. A double tyrosine phosphorylation of P68 RNA helicase confers resistance to TRAIL-induced apoptosis. Oncogene. 2007 Sep 6;26(41):6082-92. Epub 2007 Mar 26. Huang Y, Liu ZR. The ATPase, RNA unwinding, and RNA binding activities of recombinant p68 RNA helicase. J Biol Chem. 2002 Apr 12;277(15):12810-5 Wang H, Gao X, Huang Y, Yang J, Liu ZR.. P68 RNA helicase is a nucleocytoplasmic shuttling protein. Cell Res. 2009 Dec;19(12):1388-400. Epub 2009 Sep 29. Liu ZR. p68 RNA helicase is an essential human splicing factor that acts at the U1 snRNA-5' splice site duplex. Mol Cell Biol. 2002 Aug;22(15):5443-50 Carter CL, Lin C, Liu CY, Yang L, Liu ZR.. Phosphorylated p68 RNA helicase activates Snail1 transcription by promoting HDAC1 dissociation from the Snail1 promoter. Oncogene. 2010 Sep 30;29(39):5427-36. Epub 2010 Aug 2. Guil S, Gattoni R, Carrascal M, Abián J, Stévenin J, Bach-Elias M. Roles of hnRNP A1, SR proteins, and p68 helicase in c-H- Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 46 DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5) Liu ZR Guo J, Hong F, Loke J, Yea S, Lim CL, Lee U, Mann DA, Walsh MJ, Sninsky JJ, Friedman SL.. A DDX5 S480A polymorphism is associated with increased transcription of fibrogenic genes in hepatic stellate cells. J Biol Chem. 2010 Feb 19;285(8):5428-37. Epub 2009 Dec 17. splicing by modulating a stem-loop structure at the 5' splice site. Mol Cell Biol. 2011 May;31(9):1812-21. Epub 2011 Feb 22. Kar A, Fushimi K, Zhou X, Ray P, Shi C, Chen X, Liu Z, Chen S, Wu JY.. RNA helicase p68 (DDX5) regulates tau exon 10 Liu ZR. DDX5 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 5). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):44-47. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) This article should be referenced as such: 47 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(13;19)(q14;p13) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: August 2011 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1319q14p13ID1512.html DOI: 10.4267/2042/47270 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology cell commitment, and differentiation. Role in epithelial mesenchymal transition (review in Slattery et al., 2008). Clinics and pathology Disease B cell acute lymphoblastic leukemia (B-ALL) Note An apparently identical t(13;19)(q14;p13) has been described in 3 cases of chronic lymphocytic leukemia (CLL) (Finn et al., 1998; Merup et al., 1998; Brown et al., 1993). References Brown AG, Ross FM, Dunne EM, Steel CM, Weir-Thompson EM. Evidence for a new tumour suppressor locus (DBM) in human B-cell neoplasia telomeric to the retinoblastoma gene. Nat Genet. 1993 Jan;3(1):67-72 Finn WG, Kay NE, Kroft SH, Church S, Peterson LC. Secondary abnormalities of chromosome 6q in B-cell chronic lymphocytic leukemia: a sequential study of karyotypic instability in 51 patients. Am J Hematol. 1998 Nov;59(3):223-9 Epidemiology Only one case to date of ALL with this translocation, a 19-year-old female patient with pre-B-ALL; she achieved complete remission and (CR) was in continuing CR 10 months later, at last follow up (Barber et al., 2007). Inukai T, Inaba T, Ikushima S, Look AT. The AD1 and AD2 transactivation domains of E2A are essential for the antiapoptotic activity of the chimeric oncoprotein E2A-HLF. Mol Cell Biol. 1998 Oct;18(10):6035-43 Merup M, Jansson M, Corcoran M, Liu Y, Wu X, Rasool O, Stellan B, Hermansson M, Juliusson G, Gahrton G, Einhorn S. A FISH cosmid 'cocktail' for detection of 13q deletions in chronic lymphocytic leukaemia--comparison with cytogenetics and Southern hybridization. Leukemia. 1998 May;12(5):705-9 Genes involved and proteins Note The translocation involves TCF3 and an unknown partner. Barber KE, Harrison CJ, Broadfield ZJ, Stewart AR, Wright SL, Martineau M, Strefford JC, Moorman AV. Molecular cytogenetic characterization of TCF3 (E2A)/19p13.3 rearrangements in B-cell precursor acute lymphoblastic leukemia. Genes Chromosomes Cancer. 2007 May;46(5):47886 TCF3 Location 19p13.3 Protein The E2A gene encodes two distinct basic helix-loophelix transcription factors, E12 (ITF1) and E47 (TCF3) through alternative splicing. It forms homodimers and heterodimers with other basic helix-loop-helix transcription factors. Ubiquitously expressed during development. Role in cell growth, Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Slattery C, Ryan MP, McMorrow T. E2A proteins: regulators of cell phenotype in normal physiology and disease. Int J Biochem Cell Biol. 2008;40(8):1431-6 This article should be referenced as such: Huret JL. t(13;19)(q14;p13). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):48. 48 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(17;17)(q21;q24), del(17)(q21q24) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: August 2011 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1717q21q24ID1497.html DOI: 10.4267/2042/47271 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology RXR. At the DNA level, binds to retinoic acid response elements (RARE). Ligand-dependent transcription factor specifically involved in hematopoietic cells differentiation and maturation. Clinics and pathology Disease Acute myeloid leukaemia, M3 subtype (M3-AML) PRKAR1A Epidemiology Location 17q24.2 Protein Contains two tandem cAMP-binding domains. Forms heterotetramers with PRKACA (protein kinase, cAMPdependent, catalytic, alpha), also called PKA. Interacts with RARA, and regulates RARA transcriptional activity. Only one case to date, a 66-year-old male patient (Catalano et al., 2007). Cytology Auer rods and fagot cells were absent. Evolution Complete remission was obtained with ATRA, and the patient remains healthy 2 years after the diagnosis. Result of the chromosomal anomaly Cytogenetics Cytogenetics morphological Hybrid gene Cryptic deletion, FISH studies are needed to uncover the rearrangement. Description 5' PRKAR1A - 3' RARA. When we look closely to the DNA sequences at the fusion breakpoints, they correspond to the very end of exon 1 in PRKAR1A (AGAGGTTGGAGAAG) and the very begining of exon 2 in RARA (ATTGAGACCCAGAGCAGCAGT, see sequences in Ensembl), although they were described in exon 2 and exon 3 in the first and only report of this rearrangement (Catalano et al., 2007). Genes involved and proteins RARA Location 17q21.1 Protein Contains Zn fingers and a ligand binding region. Receptor for retinoic acid. Forms heterodimers with Fusion protein See figure 5' PRKAR1A - 3' RARA. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 49 t(17;17)(q21;q24), del(17)(q21q24) Huret JL differential regulation of alternately spliced messenger ribonucleic acids. Endocrinology. 1997 Jan;138(1):169-81 Description The fusion protein contains the dimerization domain from PRKAR1A fused to the Zn fingers and ligand binding regions from RARA. Catalano A, Dawson MA, Somana K, Opat S, Schwarer A, Campbell LJ, Iland H. The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia. Blood. 2007 Dec 1;110(12):4073-6 References This article should be referenced as such: Solberg R, Sandberg M, Natarajan V, Torjesen PA, Hansson V, Jahnsen T, Taskén K. The human gene for the regulatory subunit RI alpha of cyclic adenosine 3', 5'-monophosphatedependent protein kinase: two distinct promoters provide Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Huret JL. t(17;17)(q21;q24), del(17)(q21q24). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):49-50. 50 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Deep Insight Section MicroRNAs and Cancer Federica Calore, Muller Fabbri Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA (FC, MF) Published in Atlas Database: August 2011 Online updated version : http://AtlasGeneticsOncology.org/Deep/MicroRNAandCancerID20101.html DOI: 10.4267/2042/47272 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Keywords: microRNAs, non-coding RNAs, cancer, solid tumors, hematological malignancies, oncogene, tumor suppressor gene, angiogenesis, metastasis, therapy, biomarkers. Abstract MicroRNAs (miRNAs) are non-coding RNAs (ncRNAs) with gene expression regulatory functions, whose deregulation has been documented in almost all types of human cancer (both solid and hematological malignancies), with respect to the non-tumoral tissue counterpart. After the initial discovery that the miRNome (defined as the full spectrum of miRNAs expressed in a specific genome) is de-regulated in cancer, contributes to human carcinogenesis, and to the mechanisms of angiogenesis and metastases (which are hallmarks of the malignant phenotype), new pieces of evidence have been provided that miRNAs can be detected in several human body fluids, and can also be successfully used as tumor biomarkers with diagnostic, prognostic and theranostic implications. These findings have cast a new “translational” light on the research in the miRNA field, providing the rationale for a miRNA-based cancer therapy. of different species. It has been demonstrated that each miRNA can have hundreds of different targets and that approximately 30% of the genes are regulated by at least one miRNA (Bartel, 2004). MiRNAs are known to be involved in several biological processes such as cell cycle regulation, proliferation, apoptosis, differentiation, development, metabolism, neuronal patterning and aging (Bartel, 2004; Bagga et al., 2005; Harfe, 2005; Boehm and Slack, 2006; Calin et al., 2006; Arisawa et al., 2007; Carleton et al., 2007). The biogenesis of miRNAs starts in the nucleus (Figure 1), where for the most part an RNA polymerase II transcribes long primary precursors, up to several kilobases (pri-miRNAs) (Ambros and Lee, 2004). Such transcription occurs at the level of genomic regions located within the introns or exons of protein-coding genes (70%) or in intergenic areas (30%) (de Yebenes and Ramiro, 2010). Long, capped and polyadenylated pri-miRNAs (Cai et al., 2004) are then processed by a ribonuclease III (Drosha) and by the double-stranded DNA binding protein DGCR8/Pasha, which enzymatically cut Introduction Tumor formation and progression is a complex multistep process characterized by several consecutive events: accumulation of genomic alterations, uncontrolled proliferation, angiogenesis, invasion and metastasis. Over the past few years an increasing number of studies have highlighted the key role that microRNAs have in the regulation of processes described above. MicroRNAs (miRNAs) are a family of single-stranded non-coding RNAs (ncRNAs) between 19-24 nucleotides in length that regulate the expression of target mRNAs both at transcriptional and translational level. In plants such regulation occurs by perfect basepairing, usually in the 3' untranslated region (UTR) of the targeted mRNA, whereas in mammals the basepairing is only partial (Lagos-Quintana et al., 2001; Lee and Ambros, 2001; Hu et al., 2010). Evolutionarily conserved among distantly related organisms (Ambros, 2003), miRNA genes represent approximately 1% of the predicted genes in the genome Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 51 MicroRNAs and Cancer Calore F, Fabbri M Figure 1. MiRNA biogenesis. MiRNA biogenesis begins inside the nucleus, then its processing and maturation take place in the cytoplasm of an eukaryotic cell. MiRNAs are transcribed by RNA polymerase II as long primary transcript (pri-miRNAs) characterized by hairpin structure and then cleaved by the enzyme Drosha in smaller molecules of nearly 70-nucleotides (pre-miRNAs). These precursors are then exported to the cytoplasm by the Exportin 5/Ran-GTP complex and further processed by RNAse III Dicer, which generates double-stranded-RNAs called duplex miRNA/miRNA* of 22-24 nucleotides. The strand corresponding to the mature miRNA is incorporated into a large protein complex named RISC (RNA-induced silencing complex) and they interact with the 3’ UTR of the targeted messenger RNA: if the complementarity between miRNA and the 3’UTR is perfect the latter is cleaved by RISC, whereas if the matching is imperfect then translational repression occurs. them into smaller fragments of 70-100 nucleotides (pre-miRNAs) (Ambros, 2004). Precursor molecules are then exported to the cytoplasm by Exportin 5 in a Ran-GTP-dependent manner (Allawi et al., 2004; Bohnsack et al., 2004) and through an additional step mediated by the RNAse III Dicer 22 nucleotides double-strand RNAs are generated (Bartel, 2004; Esquela-Kerscher et al., 2005). The duplex miR/miR* are finally incorporated into a large protein complex named RISC (RNA-induced silencing complex): the strand of the duplex which represents the mature miRNA remains stably associated with RISC and drives the complex to the target mRNA. If the basepairing between miRNA and the 3' UTR of the target mRNA is perfect, the messenger is cleaved and degraded (as it occurs in plants), if the complementarity pairing is partial, translational silencing occurs without mRNA degradation (mechanism described in animals) (Achard et al., 2004; Gregory et al., 2006) (Figure 1). The involvement of miRNAs in cancer arises from the observation that these small molecules are differentially expressed in neoplastic tissues in a tumor-specific Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) manner when compared to normal tissues (Volinia et al., 2006), and in primary tumors when compared to metastatic tissues (Tavazoie et al., 2008). Moreover the genomic localization of miRNAs often corresponds to tumor-associated regions, characterized by chromosomal translocations, genomic amplifications, fragile sites, breakpoint regions in proximity to oncogenes (OGs) or tumor suppressor genes (TSGs) (Calin et al., 2004). In 2002 Calin et al. showed that miR-15a and miR-16-1 genes are located at a chromosomic region (13q14) deleted in more than half of B cell chronic lymphocytic leukemias (B-CLL) and that both genes are deleted or down-regulated in the majority of CLL cases (68%) (Calin et al., 2002). Based on the miRNA profiling analysis the following studies aimed at investigating the functional role of these molecules in tumorigenesis by using various approaches, which have shed light on a more complex role of miRNAs in cancer development: depending on the context they can act as OGs or TSGs, and some of them can even have a dual role of OG/TSG (Calin et al., 2007) (Table 1). 52 MicroRNAs and Cancer microRNA Dysregulation in cancer Calore F, Fabbri M miRNA target Function Reference(s) miR-155 Upregulated in Burkitt's lymphoma, Hodgkin disease, primary mediastinal c-maf non Hodgkin's lymphoma, CLL, AML, lung, breast, pancreatic cancer Oncogene Metzler, Kluiver, Calin, Garzon, Volinia, Greither miR-21 Upregulated in glioblastoma, CLL, PTEN, AML, prostate, pancreatic, gastric, PCDC4, colon, breast, lung, liver cancer TPM1 Oncogene Meng, Frankel, Zhu, Ciafre, Calin, Garzon, Volinia, Meng miR-17-92 cluster Upregulated in breast, colon, lung, pancreatic, prostate, gastric cancers, PTEN, Bim Oncogene lymphomas Volinia, Venturini miR-372/373 Upregulated in testicular tumor Oncogene Voorhoeve miR-221/222 Upregulated in thyroid, prostate, P27Kip1 glioblastoma, colon, pancreas, stomach Oncogene Visone, Galardi, le Sage miR-10b Upregulated in breast cancer HOXD10 Oncogene Ma Downregulated in CLL, prostate BCL2, CCND1, WNT3A Tumorsuppressor gene Bullrich, Cimmino, Bonci miR-15a miR-16-1 and LATS2 miR-29 family Downregulated in lung cancer, CLL, TCL1, AML, breast cancer and MCL1, cholangiocarcinoma DNMT3s Tumorsuppressor gene Calin, Iorio, Garzon, Mott, Fabbri, Pekarsky Let-7 family C-MYC, Downregulated in lung and breast HMGA2, cancer MYCN Tumorsuppressor gene/oncogene Johnson Sampson, Lee, Buechner, Brueckner, Iorio miR-34 family Downregulated in lung and pancreatic BCL2, cancer MYCN Tumorsuppressor gene Gallardo, Cole Tumorsuppressor gene Michael, Akao, Ibrahim miR-143 and Downregulated in colorectal cancer 145 cluster ERK5, C-MYC Table 1. The main de-regulated miRNAs in cancer. Legend: CLL= chronic lymphocytic leukemia; AML= acute myeloid leukemia. Moreover the use of miR-155 knock out mouse model has revealed that miR-155 is strongly implicated into the induction of Th2 lymphocyte differentiation and altered cytokine production (de Yebenes and Ramiro, 2010). Another miRNA which displays an oncogenic role is miR-21. Chan et al. demonstrated that knockdown of miR-21 in multiple glioblastoma cells induced caspase activation and apoptosis, indicating that miR-21 could function as an oncogene by blocking expression of critical apoptosis-related genes (Abdellatif, 2010). In fact miR-21 targets TSGs such as PTEN (phosphatase and tensin homolog) (Choong et al., 2007), PDCD4 (programmed cell death 4) (Dillhoff et al., 2008) and TPM1 (tropomyosin 1) (Beitzinger et al., 2007). Similarly to miR-155 it is expressed in a wide range of tumors such as glioblastoma (Ciafre et al., 2005), CLL (Calin et al., 2005), AML (Calin et al., 2008), prostate, pancreatic, gastric, colon, breast, lung (Costinean et al., 2006) and liver cancer (Choong et al., 2007). miRNAs as oncogenes Profiling studies have revealed that several miRNAs show oncogenic properties. One of the first oncomiR identified was miR-155 (Metzler et al., 2004; Kluiver et al., 2005). It is located on chromosome 21 in a host non-coding RNA called the B cell integration cluster (BIC) and is highly expressed in pediatric Burkitt's lymphoma (Metzler et al., 2004), Hodgkin disease (Kluiver et al., 2005), primary mediastinal nonHodgkin's lymphoma (Calin et al., 2005) , chronic lymphocytic leukemia (CLL) (Kluiver et al., 2005), acute myelogenous leukemia (AML) (Calin et al., 2008), lung, breast and pancreatic cancer (Volinia et al., 2006; Greither et al., 2010). A study conducted by Costinean et al. showed that transgenic mice with a Bcell targeted overexpression of miR-155 develop a lymphoproliferative disease (polyclonal pre-leukemic pre-B-cell proliferation followed by full-blown B-cell malignancy) resembling the human diseases, indicating that the deregulation mediated by miR-155 involves both the initiation and progression of the disease (Costinean et al., 2006). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 53 MicroRNAs and Cancer Calore F, Fabbri M MCL1 and TCL1 (Costinean et al., 2006; Mott et al., 2007). Among the tumor suppressor miRNAs there is the let-7 family. Johnson et al. demonstrated an inverse correlation between the expression of the let-7 family members and the expression of the oncogene RAS in lung cancer tissue (Adai et al., 2005). Let-7 family targets as well other onco-genes such as C-MYC (Sampson et al., 2007), HMGA2 (high mobility group A2) (Barakat et al., 2007) and MYCN (Buechner et al., 2011). However, not all the members of this family display a tumor suppressor role since in lung adenocarcinoma let-7a-3 has an oncogenic function and promotes tumor cell proliferation (Brueckner et al., 2007). The miR-34 family (comprising miR-34a, -34b and 34c) is downregulated in lung cancer tumor cells with respect to normal tissue and their re-expression in pancreatic cancer cell lines inhibits cell growth and invasion, and induces apoptosis and cell cycle arrest in G1 and G2/M (Gallardo et al., 2009). Similarly to the tumor suppressor miRNAs described above, the miR34 family exerts its function by targeting anti apoptotic mRNAs such as BLC2 and MYCN (Camps et al., 2008). The list of miRNAs having a tumor suppressor function ends with the cluster miR-143 and -145. These miRNAs, downregulated in several tumors (Akao et al., 2007; Banaudha et al., 2011), have been found to target ERK5 (extracellular signal-regulated kinase 5) and cMYC with consequent inhibition of tumor proliferation and increased apoptosis (Akao et al., 2007; Ibrahim et al., 2011). The miR-17-92 cluster is characterized by six miRNAs (miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1 and miR-92-1) highly expressed in breast, colon, lung, pancreatic, prostate and gastic cancer, lymphomas (Costinean et al., 2006; Nagel et al., 2007). It has been demonstrated that the miR-17-92 cluster induces B cell proliferation. Moreover, transgenic mice overexpressing miR-17-92 in lymphocytes developed lymphoproliferative disease and autoimmunity through the inhibition of tumor suppressor Pten and the proapoptotic protein Bim (de Yebenes and Ramiro, 2010). Other miRNAs that have an oncogenic role are miR372/373, which are involved in the development of human testicular germ cell tumors by neutralizing the TP53 pathway (Voorhoeve et al., 2006), miR-221/222 which induce proliferation of thyroid (Iorio et al., 2007), prostate (Galardi et al., 2007) and glioblastoma (Bai et al., 2007), miR-10b which promotes cell migration and invasion in breast cancer (Derby et al., 2007). miRNAs as tumor suppressor genes If several miRNAs are known for their pro-oncogenic role, then other miRNAs represent their counterpart by acting as a TSG. Their silencing due to mutations, chromosomal rearrangements or to promoter methylation (Calin et al., 2002; Calin et al., 2005; Ishii and Saito, 2006; Arisawa et al., 2007) contributes to the initiation and progression of cancer. MiR-15a and miR-16-1 represent a typical example of TSG miRNA. Encoded as a cluster at the level of chromosome 13q14.3, a region frequently deleted in chronic lymphocytic leukemia (CLL) (Bullrich et al., 2001), miR-15a and -16 display expression levels inversely correlated to the BCL2 ones. These miRNAs in fact induce apoptosis in leukemic cells by directly targeting the anti-apoptotic gene (Calin et al., 2005). Moreover, it has been demonstrated that miR-15a and 16 exert a tumor-suppressor role also in prostate cancer by targeting BCL2, CCND1 (cyclin D1) and WNT3A (encoding a protein which promotes cell survival, proliferation and invasion) (Bonci et al., 2008). Taken together, these findings harbor therapeutic implications and bring new insights to the comprehension and treatment of cancer. Chromosome 7q32 hosts the miR-29 family (comprising miR-29a, -29b and -29c), which is downregulated in lung cancer, CLL, AML, breast cancer and cholangiocarcinoma (Calin et al., 2005; Mott et al., 2007; Calin et al., 2008). It has been demonstrated that in lung cancer the expression of miR-29 family members is inversely correlated with DNMT3A and -3B (DNA methyltransferases 3A and 3B) and that these miRNAs directly target these enzymes, inducing global hypomethyation of tumoral cells (Calin et al., 2007) and reactivation of methylation-silenced TSGs such as WWOX, FHIT, Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) miRNAs in solid tumors Lung cancer Lung cancer is the leading cause of cancer death around the world (Jemal et al., 2009). Gao et al. performed miRNA microarray expression profiling in order to compare miRNAs expression in primary squamous cell lung carcinoma with normal cells and determine miRNA potential relevance to clinicopathological factors and patient postoperative survival times. They found out that miR-21 was upregulated in nearly 75% of cancer specimens and that this modulation was significantly correlated with shortened survival time (Cheng et al., 2011). Yanaihara and co-workers used the same approach and correlated miRNA expression profiles with survival of lung cancer, finding out that high miR-155 and low let7a-2 expression were correlated with poor survival. Furthermore, they found a molecular signature for subset of lung cancer: they identified six miRNAs having a differential expression in adenocarcinoma and squamous cell cancer (mir-205, mir-99b, mir-203, mir-202, mir-102, and mir-204-Prec). Among these, the expression of miR-99b and miR-102 was found higher in adenocarcinoma (Volinia et al., 2006). 54 MicroRNAs and Cancer Calore F, Fabbri M IGF1R, SP1), inducing an upregulation of the tumor suppressor gene BRCA1 (Heyn et al., 2011). Colorectal cancer In 2008 a study conducted by Schetter et al. the authors performed miRNA microarray expression profiling comparing 84 pairs of tumors (colon adenocarcinoma) and adjacent non-tumoral tissues (Schetter et al., 2008). They found 37 differentially expressed miRNAs; among them miR-20a, -21, -106, -181b and -203 levels were higher in tumor specimens. The overexpression of miR-21 and its role in tumor proliferation in several kind of cancers has already been described before. Also miR-20a belongs to the miR-17-92 cluster, whose overexpression promotes cell proliferation (Hayashita et al., 2005) and increased tumor size. One of the most recent tumor suppressor miRNAs found in colorectal cancer is miR-137. Balaguer et al. reported that this miRNA is constitutively expressed in the normal colonic epithelium but during the early events of colorectal carcinogenesis it is silenced through promoter hyper-methylation. Moreover, its reexpression in vitro inhibits cell proliferation in a cell specific manner. These findings suggest a prognostic role for miR-137 (Balaguer et al., 2010). It has been recently demonstrated by Sarver et al. that miR-183 has an oncogenic role in colon cancer (but also in synovial sarcoma and rhabdomyosarcoma) through its regulation of the expression levels of 2 tumor suppressor genes, EGR1 and PTEN. The authors also provided evidence that knockdown of miR-183 affects cellular migration and they suggest that pharmaceutical intervention on tumor characterized by the upregulation of miR-183 may be useful as anticancer therapy (Chen et al., 2010). Hepatocellular carcinoma One of the most common malignant tumors is hepatocellular carcinoma. Murakami et al. analysed the miRNA expression profiles in 25 specimens of hepatocellular carcinoma compared with adjacent nontumoral tissues and nine chronic hepatitis specimens (Murakami et al., 2006). miR-222, miR-17-92 and miR-106a exhibited higher expression in tumor tissues than in the normal ones and were found associated with the tumor differentiation status. Pineau et al. performed profiling studies on 104 hepatocellular carcinoma tissue specimens, 90 cirrhotic, 21 normal and 35 hepatocellular carcinoma cell lines (Pineau et al., 2010). They found a 12 miRNA signature that characterizes tumor progression starting from normal liver, to cirrhosis to full blown tumor. Among them, miR-21, miR-221/222, miR-34a and miR-224 were found overexpressed in the progression signature. miR-224 overexpression is connected with the regulation of cell proliferation, cell migration and metastasis (Chemistry, 2010). Su et al. reported that miR-101 is significantly downregulated in hepatocellular carcinoma and that its overexpression inhibits tumor development in nude Yu et al. found a five-microRNA signature (let-7a, miR-21, miR-137, miR-372, miR-182*) associated with survival and cancer relapse in NSCLC (non-small cell lung cancer) patients (Abdurakhmonov et al., 2008). Another specific marker for squamous cell lung carcinoma is miR-205, according to a microarray study performed by Lebanony et al., who found a strong association between the expression levels of miR-205 and squamous cell lung carcinoma histology (Barshack et al., 2010). In addition to the already mentioned miRNAs, miR-31 is found to act as an oncogenic miRNA by targeting mRNAs encoding two anti-tumoral proteins, LATS2 (large tumor-suppressor 2) and PPP2R2A (PP2A regulatory subunit B alpha isoform) (Anand et al., 2010). Chou and co-workers discovered that miR-7 promotes EGFR-mediated tumorigenesis in lung cancer by targeting ERF (Ets transcriptional repressor) thus modulating cell growth (Choudhry and Catto, 2011). However, miR-7 seems to have a dual function of oncogene/tumor-suppressor miRNA. Xiong et al. indeed found that overexpression of miR-7 in NSCLC A549 cells inhibits cells proliferation and induces apoptosis by targeting anti-tumoral protein Bcl-2 (Shao et al., 2011). Another miRNA that displays a tumor-suppressor role in lung cancer is miR-451. Wang et al. demonstrated not only that this miRNA is the most downregulated in NSCLC tissues, but also that it regulates survival of cells partially through the downregulation of the oncogene RAB14 (Ras-related protein 14) (Bian et al., 2011). Breast cancer Breast cancer is the second leading cause of cancer deaths in the developed world and the most commonly diagnosed cancer in women (Bonev et al., 2011). A miRNA expression profile study for breast cancer was conducted by Iorio et al. The authors found 13 miRNAs differentially expressed between tumor and normal tissues: among the upregulated ones there were oncogenic miR-21 and miR-155, while miR-10b, let-7 miR-125b, miR-145 and miR-205 were found downregulated (Calin et al., 2005). The latter directly targets HER3 receptor and blocks the activation of downstream Akt, inhibiting cell proliferation. Moreover, miR-205 sensitizes cells to Gefitinib and Lapatinib, two tyrosine-kinase inhibitors, promoting apoptosis (Iorio et al., 2009). Shi et al. found that miR-301 has an oncogenic role in breast tumor by targeting FOXF2, BBC3, PTEN and COL2A1. Its upregulation promotes proliferation, migration, invasion and tumor formation. Moreover, by cooperating with its host gene SKA2, miR-301 promotes the aggressive breast cancer phenotype with nodal or distant relapses (Akao et al., 2011). Heyn and co-workers identified miR-335 as a tumorsuppressor gene. It controls different factors of the upstream BRCA1 regulatory pathway (such as ERa, Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 55 MicroRNAs and Cancer Calore F, Fabbri M of the normal allele in leukemic cells of two CLL patients, one of which with a family history of CLL and breast cancer (Calin et al., 2005). A similar point mutation, adjacent to the miR-16-1 locus has been described in the CLL prone New Zealand Black mouse strain model (Raveche et al., 2007). One of the most frequent molecular hallmarks of the malignant, mostly non-dividing B-cell of CLL, is the up-regulation of the antiapoptotic BCL2. It has been demonstrated that both miR-15a and miR-16 directly target BCL2 in CLL both in vitro and in vivo (Calin et al., 2005; Ambs et al., 2008), therefore suggesting that the miR-15a/16-1 cluster enacts a tumor suppressor function. Clinicians are aware that CLL is characterized by recurrent and common chromosomal aberrations, which harbor prognostic implications. Some of the most frequent of these abnormalities are the 13q deletion, the 17p deletion and the 11q deletion. While CLL patients with the 13q deletion experience the indolent form of the disease (characterized by IGVH mutated and low levels of the prognostic surrogate marker ZAP70), those with the 17p or the 11q deletion (alone or in association with the 13q), experience an aggressive form of the disease (characterized by IGVH unmutated and high levels of ZAP70) (Chiorazzi et al., 2005). Recently, a new molecular network explaining the role of these chromosomal aberrations and their prognostic implications for human CLL has been described. According to this model, the miR-15a/16-1 cluster (located at 13q), directly targets the pro-apoptotic TP53 (located at 17p), which in turn transactivates the miR34b/34c cluster (located at 11q), directly targeting ZAP70 (Fabbri et al., 2011). Also, TP53 is able to transactivate the miR-15a/16-1 cluster, creating a feedforward regulatory loop (Fabbri et al., 2011). These findings identify for the first time some of the molecular effectors connecting these three recurrent chromosomal aberrations in CLL and can explain both their prognostic implications and the observed levels of ZAP70 according to the degree of aggressiveness of the disease. Recently, Klein et al. (Danilov et al., 2010) generated two groups of transgenic mice models: one mimicking the MDR and the other containing a specific deletion of the miR-15a/16-1 cluster. Although the same spectrum of clonal lymphoproliferative disorders was observed in both animal models, the disease was more aggressive in the MDR group than in the miR15a/16-1 group, suggesting that additional genetic elements in the 13q14 region may affect the severity of the disease. The oncogene TCL1 (T-cell leukemia/lymphoma 1A) is over-expressed in the aggressive CLL (Herling et al., 2006; Barlev et al., 2010), and is regulated by miR-29b and miR-181b (Costinean et al., 2006). Furthermore, miR-181a directly targets BCL2 (Ebert et al., 2007), suggesting a central role of miR-181 family and of the miR-15a/16-1 cluster in regulating BCL2 expression in CLL. Stamatopoulos et al. (Stamatopoulos et al., 2009) found that downregulation of miR-29c and miR-223 are mice, sensitizes tumor cell lines to serum starvation and chemotherapeutic treatment (Su et al., 2009). Other tumor suppressor miRNAs are: miR-122, normally downregulated in hepatocellular carcinoma, whose overexpression induces apoptosis and cell cycle arrest through targeting of BCLW (Chemistry, 2010); miR-198, which inhibits migration and invasion in a cMET dependent manner (Akao et al., 2011); miR-125b, which suppresses tumor cell growth in vitro and in vivo and induces cell cycle arrest at G1/S acting as a tumor suppressor gene through the suppression of LIN28B (Bates et al., 2010), a promoter of cell proliferation and metastasis through regulation of c-MYC and ECadherin (Ai et al., 2010). miRNAs in hematological malignancies Similarly to what has been reported in solid tumors, also in hematological malignancies the miRNome is frequently de-regulated with respect to the normal cell counterpart. Physiologic variations in miRNA expression occur during normal hematopoiesis, and affect differentiation and commitment of the multipotent hematologic progenitor (MPP). Hematologic tumors represent abnormal blocks in hematopoiesis. Interestingly, the aberrations of the miRNome occurring in these tumors can be explained, at least in some instances, as the result of the block of differentiation leading to the development of the malignancy. In other cases, the cause of the observed de-regulation has not been clarified, but the role of the de-regulated miRNAs in the acquisition of the malignant phenotype has been understood, based on the nature of the targeted genes. miRNAs in leukemias Chronic lymphocytic leukemia (CLL) is the most frequent leukemia of the adult in the Western world. Chromosomal aberrations recur in human CLL and harbor diagnostic and prognostic implications. Occurring in about 65% of cases, the 13q14 deletion is the most frequent chromosomal aberration observed in human CLL. Based on the analysis of a large number of CLL cases with monoallelic 13q14 deletion, a minimal deleted region (MDR) has been defined. This MDR includes a long ncRNA, called DLEU2 (deleted in leukemia 2), strongly conserved among vertebrates, and the first exon of the DLEU1 gene, another ncRNA (Migliazza et al., 2001; Chai et al., 2010). The miR15a/16-1 cluster is located within intron 4 of DLEU2, and genetic alterations affecting DLEU2 mRNA expression would also affect miR-15a/16-1 cluster expression (Calin et al., 2002) . Therefore, the expression of miR-15a/16-1 is reduced in the majority of CLL patients carrying the 13q deletion (Calin et al., 2002). Interestingly, the same miRNA cluster is involved in cases of familial CLL, since a germ-line mutation in the sequence of pre-miR-16-1 (which leads to a reduced miR-16 expression both in vitro and in vivo), has been identified associated with the deletion Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 56 MicroRNAs and Cancer Calore F, Fabbri M leukemia (ALL) (Zanette et al., 2007; Nagel et al., 2009). Recently, the miR-17–92 cluster has been correlated with the development of mixed lineage leukemia (MLL)-rearranged acute leukemia (Chemistry, 2010). Up-regulation of this cluster was observed not only in MLL-associated AML, but also in ALL, and is possibly due to both DNA copy number amplification at 13q31 and to direct upregulation by MLL fusions (Chemistry, 2010). Interestingly, a specific miRNA signature of 4 miRNAs is able to distinguish the two forms of acute leukemias (ALL from AML (acute myeloid leukemia)) with an accuracy rate of 98%. Indeed, higher expression of miR-128a and miR-128b was found in ALL compared to AML, whereas down-regulation of let-7b, miR-223 indicates ALL vs AML (Science, 2007). At the moment, the leukemogenic mechanism of miR-128b is still poorly understood. Zhang et al., have identified a miRNA signature in children with ALL complicated by central nervous system (CNS) relapse (Ai et al., 2009). The high-risk-of-relapse signature is composed of overexpression of miR-7, miR-198, and miR-663, and down-regulation of miR-126, miR-345, miR-222, and miR-551a. MiR-16 has a prognostic significance in ALL. Indeed, Kaddar et al., found that low expression of miR-16 is associated with a better ALL outcome (Kaddar et al., 2009). In AML with normal karyotype high levels of miR-10a, -10b, members of let-7 and miR-29 families, and downregulation of miR-204, identify NPM1 (nucleophosmin-1) mutated versus unmutated cases (Calin et al., 2008). Recently, Ovcharenko et al., confirmed that miR-10a expression is highly characteristic for NPM1 mutated AML, and may contribute to the intermediate risk of this condition by interfering with the TP53 machinery, partly regulated by its target MDM4 (murine double minute 4) (Ovcharenko et al., 2011). Over-expression of miR-155 is associated with FLT3-ITD+ status, although there is evidence that this up-regulation is actually independent from FLT3 signaling (Calin et al., 2008). The fusion oncoprotein AML1/ETO (generated by the t(8;21) translocation), is the most frequent chromosomal abnormality in AML, and causes epigenetic silencing of miR-223, by recruiting chromatin remodeling enzymes at an AML1-binding site on the pre-miR-223 gene (Fazi et al., 2007). By silencing miR-223 expression, the oncoprotein inhibits the differentiation of myeloid precursors (promoted by high levels of miR-223), therefore actively contributing to the pathogenesis of this myeloproliferative disorder. A central role in the pathogenesis of AML is also played by miR-29b, a direct regulator of the expression of all three DNA methyltransferases (Calin et al., 2007; Garzon et al., 2009b). Re-expression of miR-29b induces de-methylation and re-expression of epigenetically silenced TSGs, such as ESR1 (estrogenreceptor alpha), and p15 (INK4b) (Garzon et al., 2009b). Moreover, restoration of miR-29b in AML cell predictive of treatment-free survival (TFS) and overall survival (OS). Low expression of miR-223, miR-29b, miR-29c, and miR-181 family are associated with disease progression in CLL cases harboring the 17p deletion, whereas patients carrying the trisomy 12 abnormality and high expression of miR-181a experience a more aggressive variant of CLL (De Martino et al., 2009). Interestingly, the miR-29 family has been demonstrated to control key epigenetic mechanisms (such as the expression of all three main DNA methyltranferases) both in solid tumors and in hematological malignancies (Calin et al., 2007; Garzon, 2009), therefore suggesting the involvement also of miRNA-mediated epigenetic factors in the pathogenesis and prognosis of human CLL. Also miR-155 is up-regulated in CLL versus normal CD19+ B lymphocytes, suggesting that this miRNA might act as diagnostic biomarker of CLL (Marton et al., 2008). The Philadelphia chromosome (reciprocal translocation t(9;22)) is the hallmark of the chronic myeloid leukemia (CML), generating the chimeric protein BCRABL1, which is able to activate the miR-17-92 cluster, together with the oncogene c-MYC, during the early chronic phase, but not in blast crisis CML CD34+ cells (Nagel et al., 2007). These findings suggest that the miR-17-92 cluster contributes to early phase CML pathogenesis, harboring CML diagnostic biomarker properties. ABL1 is also a direct target of miR-203, whose over-expression inhibits cancer cell proliferation in an ABL1-dependent manner (Bueno et al., 2008). Moreover, it has been shown that Philadelphia positive CMLs, often present a reduced expression of miR-203 because of its promoter hyper-methylation, while no methylation can be detected in other hematological malignancies that do not carry ABL1 alterations (Bueno et al., 2008). Finally, down-regulation of miR10a has been observed in about 70% of CMLs, with an inverse correlation with the expression of the oncogene USF2 (upstream stimulatory factor 2) (Agirre et al., 2008). Overall, high levels of miR-17-92 cluster and low expression of miR-203 and miR-10a seem to be part of the diagnostic signature of human CML. More recently, miR-451 has emerged as another key player in CML. Indeed this miRNA can target BCR-ABL1, which in turn can inhibit miR-451 expression, creating a regulatory loop, whose disruption might have therapeutic implications in the disease (Lopotova et al., 2011). Another gene which inhibits cell growth and is frequently down-regulated in CML is CCN3 (also known as NOV or nephroblastoma overexpressed gene). A possible mechanism of its down-regulation in CML has been recently identified and is mediated by miR-130a and miR-130b, which are up-regulated by BCR-ABL1 in CML, and directly target CCN3, contributing to leukemic cell proliferation (Suresh et al., 2011). Up-regulation of the miR-17-92 cluster has been described also in B- and T-cell acute lymphocytic Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 57 MicroRNAs and Cancer Calore F, Fabbri M Indeed, miR-155 directly target SHIP (Src homology 2 domain-containing inositol-5-phosphatase), and C/EBPbeta (CCAAT enhancer-binding protein beta), two key regulators of the interleukin-6 signaling pathway, therefore triggering a chain of events that promotes the accumulation of large pre-B cells and acute lymphoblastic leukemia/high-grade lymphoma (Costinean et al., 2009). Also miR-155 knockout (KO) mice models have been generated, showing that the loss of miR-155 switches cytokine production toward TH2 differentiation (de Yebenes and Ramiro, 2010), and also compromises the ability of dendritic cells (DC) to activate T cells, because of a defective antigen presentation or abnormal co-stimulatory functions (de Yebenes and Ramiro, 2010). As observed in leukemias, also in NHLs, a specific signature of 4 de-regulated miRNAs (namely miR-330, -17-5p, -106a, and -210) can differentiate among reactive lymph nodes, follicular lymphomas (FL), and DLBCL (Hoefig et al., 2008). Noteworthy, miR-17-5p, and miR-106a belong to two paralogous clusters located on chromosome 13 and X, respectively, with a well established oncogenic role both in solid and hematological malignancies (Chang et al., 2008). The miR-17-92 cluster is located in a region frequently amplified in malignant B-cell lymphomas (Abbott et al., 2005), and is overexpressed in over 60% of B-cell lymphoma patients (Allawi et al., 2004). In murine pluripotent cells from MYC-transgenic mice, overexpression of this miRNA cluster accelerates lymphomagenesis (Allawi et al., 2004), whereas in miR-17-92 TG mice models a higher than expected rate of lymphoproliferative disorders and autoimmunity and premature death was observed (de Yebenes and Ramiro, 2010). These effects are at least in part due to the direct targeting of the PTEN and BIM, which controls B-lymphocyte apoptosis (de Yebenes and Ramiro, 2010). The miR-106a-363 polycistron is also overexpressed in 46% of acute and chronic human Tcell leukemias (Landais et al., 2007), claiming a role in leukemogenesis. Interestingly, both miR-106b-25 and miR-17-92 parologous clusters interfere with the transforming growth factor-beta (TGF-beta) signaling (Petrocca et al., 2008), which is inhibited in several tumors (Derynck et al., 2001). Moreover, Ventura et al. have shown that the miR-17-92 and miR-106b-25 double knockout mouse model has a more severe phenotype than the miR-17-92 single knockout mouse model (Ventura et al., 2008), suggesting that both clusters are implicated in the control of apoptosis in malignant lymphocytes. Interestingly, miR-17-5p and miR-20a (which belong to the miR-17-92 cluster) are induced by the proto-oncogene and transcription factor c-MYC (Nakamoto et al., 2005), and in turn the cluster directly targets E2F1, a c-MYC transactivated transcription factor promoting cell-cycle progression (Nakamoto et al., 2005). Therefore, the miR-17-92 cluster tightly regulates c-MYC-driven cell-cycle progression. From a more translational perspective, it lines and primary samples, suppresses the expression of OGs such as MCL1, CXXC6, and CDK6, which are direct targets of miR-29b (Garzon et al., 2009a). Abnormal activation of the proto-oncogene c-KIT contributes to leukemogenesis. Gao et al., found that miR-193a is silenced by promoter hyper-methylation in AML, and since this miRNA directly targets c-KIT, this epigenetic silencing is responsible, at least in part, for the aberrant up-regulation of the oncogene in AML (Cheng et al., 2011). Indeed, restoration of miR-193a expression by de-methylating agents, reduces the expression of c-KIT and induces cancer cell apoptosis and granulocytic differentiation (Cheng et al., 2011). Similarly, also miR-193b directly targets c-KIT in AML (Cheng et al., 2011). By using a novel approach based on the integration of miRNA and mRNA expression profiles, Havelange et al., found a strong positive correlation between miR-10 and miR-20a and HOX-related genes, a significant inverse correlation between genes involved in immunity and inflammation (such as IRF7 and TLR4) and a panel of 4 miRNAs (namely, miR-181a, -181b, -155, and -146), and a strong direct correlation between miR-23, -26a, -128a, and -145 and pro-apoptotic genes (such as BIM and PTEN) (Havelange et al., 2011). Also miR-100 has been described as an OG in AML, by targeting the TSG RBSP3 (CTD (carboxy-terminal domain, RNA polymerase II, polypeptide A) small phosphatase-like) (Cao et al., 2011). Also in AML, miR-17/20/93/106 have been shown to promote hematopoietic cell expansion by targeting sequestosome 1-regulated pathways in mice (Meenhuis et al., 2011). Downregulation of miR-29a and miR-142-3p has been observed in AML with respect to controls (Bian et al., 2011), and miR-29a contributes to counteract leukemic proliferation by directly targeting the proto-oncogene SKI (Teichler et al., 2011). miRNAs in lymphomas De-regulation of miRNAs has been reported also in non Hodgkin lymphomas (NHL) and in Hodgkin's disease (HL). The first evidence of an involvement of miRNAs in lymphomagenesis was provided by Eis et al. who observed that the final part of the B-cell integration cluster (BIC) non-coding RNA (ncRNA), where miR155 is located (Chen and Meister, 2005), was able to accelerate MYC-mediated lymphomagenesis in a chicken model (Bashirullah et al., 2003). Subsequently, high levels of BIC/miR-155 were described also in pediatric Burkitt's lymphoma (BL) (Metzler et al., 2004), in diffuse large B-cell lymphoma (DLBCL) (Lawrie, 2007; Hoefiget al., 2008), and in HL (Kluiver et al., 2005; Abdurakhmonov et al., 2008; Van Vlierberghe et al., 2009). In a B-cell specific miR-155 transgenic (TG) mouse model the onset of an acute lymphoblastic leukemia/high-grade lymphoma at approximately 9 months of age was observed (Costinean et al., 2006). In these TG mice, the B-cell precursors with the highest miR-155 expression were at the origin of the leukemias (Costinean et al., 2009). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 58 MicroRNAs and Cancer Calore F, Fabbri M has been also demonstrated that over-expression of the miR-17-92 cluster also significantly increases the resistance to radiotherapy in human mantle cell lymphoma cells (Ahn et al., 2010), revealing a role for this cluster as a theranostic biomarker. MiR-34a is negatively regulated by c-MYC (Abdurakhmonov et al., 2008). In c-MYC over-expressing B-lymphocytes miR-34a confers drug resistance by inhibiting TP53dependent bortezomib-induced apoptosis (Sotillo et al., 2011). Finally, down-regulation of miR-143 and miR145 has been described in B-cell lymphomas and leukemias (Akao et al., 2007), and re-expression of these miRNAs in a Burkitt lymphoma cell line demonstrated a dose-dependent growth inhibitory effect, mediated in part by miRNA-induced downregulation of the oncogene ERK5 (Akao et al., 2007). In HL, Navarro et al. identified a distinctive signature of 25 miRNAs able to distinguish HL from reactive lymph nodes, and 36 miRNAs differentially expressed in the nodular sclerosis and mixed cellularity subtypes of HL (Navarro et al., 2007). Interestingly, 3 miRNAs (namely, miR-96, -128a, and -128b) are selectively downregulated in HL cells with Epstein–Barr virus (EBV) infection, but only one of these miRNAs is part of the signature of 25 de-regulated miRNAs in HL versus reactive lymph nodes, suggesting that EBV might not be relevant for HL pathogenesis (Navarro et al., 2007). Down-regulation of miR-150 and overexpression of miR-155 frequently occur in HL cell lines (Gibcus et al., 2009). Since HL develops in the lymph node germinal center, and high levels of miR155 have been described in the germinal center also during normal lymphopoiesis, it can be postulated that the observed over-expression of miR-155 in HL might result from an abnormal block of lymphocyte differentiation at the germinal center level. Van Vlierberghe et al., have compared miRNA profiles of microdissected Reed-Sternberg cells and Hodgkin cell lines versus CD77+ B-cells (Van Vlierberghe et al., 2009). In this study a profile of 12 over and 3 underexpressed miRNAs was identified (Van Vlierberghe et al., 2009), showing only a partial overlap with Navarro's profile. This discrepancy might be due to the different procedure used to collect HL cells. Finally, also in HL miRNA expression profile can predict prognosis. Indeed, low levels of miR-135a are associated with a higher relapse risk and a shorter disease-free survival (Gallardo et al., 2009). A possible molecular explanation for this effect is that miR-135a directly targets the kinase JAK2 (Janus Kinase 2). Therefore, low levels of miR-135a are associated with higher expression of JAK2, which leads to upregulation of the antiapoptotic BCL-XL, therefore leading to reduced apoptosis and increased cell proliferation (Gallardo et al., 2009). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) miRNAs in body fluids as tumor biomarkers MiRNAs have been successfully detected in blood and other human fluids. It has been shown that they circulate wrapped in circulating microvescicles called "exosomes" (Bar et al., 2008), and therefore are extremely stable and resistant to degradation (Aumiller and Forstemann, 2008; Kroh et al., 2010). In 2010, Weber et al. determined miRNA expression in 12 different types of body fluids (amniotic fluid, breast milk, bronchial lavage, cerebrospinal fluid (CSF), colostrum, peritoneal fluid, plasma, pleural fluid, saliva, seminal fluid, tears and urine) collected from healthy individuals, and showed that the highest concentrations of miRNAs were found in tears and the lowest in CSF, pleural fluid and urine (Black et al., 2010). The ability to detect miRNAs in body fluids has generated interest in their possible role as tumoral biomarkers. Several studies have demonstrated that miRNAs can indeed be successfully employed both as cancer diagnostic and prognostic biomarkers both in solid and in hematological malignancies. Table 2 summarizes some of these studies. miRNAs in body fluids as tumor biomarkers in solid tumors Diagnostic biomarkers The first evidence that circulating miRNAs can be effectively used to diagnose cancer was provided by Mitchell et al. in 2008 (Bar et al., 2008). They found that higher levels of miR-141 in the serum of 25 patients affected by prostate cancer, compared with 25 healthy control donors identify patients affected by cancer with a sensitivity of 60%, and a specificity of 100% (Bar et al., 2008). Subsequently, Taylor et al. showed that a signature of 8 circulating miRNAs (enclosed in tumor-derived exosomes of endocytic origin) can be used as diagnostic biomarker of ovarian cancer (Chang et al., 2008). Moreover, in a comparison of 152 patients affected by NSCLC versus 75 healthy donors, Chen et al., identified higher levels of miR-25, and miR-223 in the serum of cancer patients (Aumiller and Forstemann, 2008). Interestingly, these Authors also demonstrated that circulating miRNAs resist treatments with HCl, NaOH, and repeated freeze and thaw cycles, therefore acting as stable, reliable biomarkers (Aumiller and Forstemann, 2008). Patients affected by pancreatic cancer have higher concentrations of circulating miR-210 (Bar et al., 2008) , -200a, and -200b (Chemistry, 2010), suggesting that these miRNAs might be used to successfully screen for pancreatic cancer. High levels of circulating miR-29a, 92 and -17-3p have been found in patients affected by colorectal cancer (Anand et al., 2010). 59 MicroRNAs and Cancer Cancer Expression cancer Calore F, Fabbri M in Biomarker property Body fluid miRNA Reference Solid Tumors Pancreas High D, D, D Blood 200a, 200b, 210 Ho, Weber Prostate High (D,P), P Blood 141, 375 Mitchell, Brase Colorectal High (D,P),D, D Blood 29a, 92, 17-3p Ng, Huang OSCC High D Blood 31 Liu Breast High (D,P),D,(D,P) Blood 21, 195, let-7a Asaga, Heneghan Lung High D,D Blood 25, 223 Lu HCC Lower ratio D Blood 92a/638 Shigoka Lung, Gastric High D,D,D Pleural effusion 24, 26a, 30d Xie Bladder High D,D,D Urine 126, 182, 199a Hanke OSCC High D Saliva 31 Liu OSCC Low D Saliva 200a, 125a Park Bladder Higher ratio D Urine 126/152 and 182/152 Hanke (D,P), (D,P), D Blood 21, 155, 210 Lawrie Hematological malignancies DLBCL High Table 2. MiRNAs detectable in body fluids and their diagnostic and prognostic significance for cancer patients. Legend: The column "Biomarker property" should be read as each letter (or in parenthesis letters) referred to the miRNA reported in the column "miRNA", according to the sequence order in which these miRNAs are reported. D= Diagnostic biomarker; P= Prognostic biomarker; (D,P)= Diagnostic and Prognostic biomarker. OSCC= Oral Squamous Cell Carcinoma; HCC= Hepatocellular Carcinoma; DLBCL= Diffuse Large B-Cell Lymphoma. Interestingly, miR-92 is not elevated in the plasma of patients with irritable bowel disease, suggesting a role for this miRNA in the differential diagnosis between this benign condition and cancer. Moreover, the increased levels of circulating miR-29a and -92 occur already in presence of pre-cancerous conditions such as colon adenomas (Anand et al., 2010), revealing that the de-regulation of these two miRNAs is an early event in colon carcinogenesis and their increased plasma concentration might be helpful for the very early (even pre-cancerous) phase of colorectal tumorigenesis. In breast cancer, Asaga et al. showed that serum concentrations of miR-21 correlates with the presence and extent of breast cancer (Asaga et al., 2011), whereas Heneghan et al., showed that circulating miR195 differentiates breast cancer from other malignancies and is a potential biomarker for the detection of non-invasive and early stage disease (Henegan et al., 2010). Finally, in oral squamous cell carcinoma (OSCC) high levels of circulating miR-31 differentiate patients from healthy controls and the concentration of this miRNA decreases after surgical resection of the tumor (Anand et al., 2010), suggesting that miR-31 might be helpful also for the early detection of OSCC recurrence. In addition to blood and plasma, miRNAs can be detected also in other body fluids and have diagnostic biomarker properties. High levels of miR-31 (Anand et al., 2010), and lower levels of miR-200a and -125a (Addo-Quaye et al., 2009) have been identified in the Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) saliva of OSCC patients. An increased expression of miR-126, -182, and -199a has been described in the urine of patients affected by bladder cancer with respect to healthy controls (Hanke et al., 2010), whereas the ratio miR-126/miR-152 and miR-182/miR152 is higher in patients affected by bladder cancer versus carriers of urinary tract infections, with a sensitivity of 72% and 55%, respectively, and a specificity of 82% (Hanke et al., 2010). Similarly, in the blood of patients with hepatocellular carcinoma (HCC), Shigoka et al. found that the ratio of miR92a/miR-638 is lower than healthy controls, suggesting a possible role of this non-coding RNA parameter in the diagnosis of HCC. Also in malignant pleural effusions of patients affected by lung cancer and gastric carcinoma, higher levels of miR-24, -26a, and -30d compared to controls were reported (Dai et al., 2010). Prognostic biomarkers In addition to their role as diagnostic biomarkers, miRNA can also act as prognostic and theranostic in several human solid tumors. Low levels of circulating let-7a are associated with node positive breast cancer, compared to negative node disease (Henegan et al., 2010), whereas higher levels of miR-21 can be detected in patients with advanced breast cancer with respect to early stage disease (Asaga et al., 2011). Similarly, circulating miR-29a expression differs in early stage versus advanced colorectal cancer (Anand et al., 2010). In prostate cancer, higher serum levels of miR-375 and -141 are found in patients with 60 MicroRNAs and Cancer Calore F, Fabbri M advanced disease (Brase et al., 2011), whereas higher circulating miR-21 was found in hormone refractory prostate cancer, with respect to benign prostatic hyperplasia, localized prostate cancer and hormone dependent prostate cancer (Bo et al., 2011). the systemic circulation distant sites in which they can finally proliferate as secondary tumors. Depending on their role in the modulation of these processes, miRNAs can be subdivided into two groups: the anti-angiogenic and the pro-angiogenic ones. Poliseno et al. demonstrated that the miR-221/miR-222 family has anti-angiogenic properties as it inhibits the angiogenic activity of stem cell factor SCF by targeting its receptor c-KIT in endothelial cells (Poliseno et al., 2006). Since miR-21 plays a crucial role in cancer progression Sabatel et al. pondered whether it could also be involved in angiogenesis (Sabatel et al., 2011). Their in vitro and in vivo study revealed that mir-21 is a negative regulator of endothelial cell migration and tubulogenesis. Angiogenesis inhibition would occur through the targeting of RhoB, a small GTPase which is responsible for the assembly of actin stress fibers (Aspenstrom et al., 2004). However, it seems that miR21 has a dual role in the regulation of angiogenesis. Liu et al. in fact found that the overexpression of miR-21 in prostate cancer cell line increases the expression of HIF-1a and VEGF through the AKT and ERK pathway, thus acting as a pro-angiogenetic miRNA (Ayala de la Pena et al., 2011). Other miRNAs are known to be positive regulators for angiogenesis. For example, in vascular endothelial cells miR-130a downregulates the expression of the antiangiogenic homeobox genes HOXA5 and GAX in response to mitogens, proangiogenic and proinflammatory factors (Aumiller and Forstemann, 2008). By using in vitro and in vivo studies Fang et al. found that miR-93 promotes angiogenesis and tumor growth by suppressing integrin-b8 expression and enhancing endothelial activity (Fang et al., 2011). Indeed this miRNA induces blood vessels formation, cell proliferation and migration by targeting the cell deathinducing antigen integrin-b8. The authors cannot exclude that miR-93 may also target other genes involved in tumorigenesis and angiogenesis. Also, the miR-17-92 cluster promotes angiogenesis by inhibiting the expression of antiangiogenic protein thrompospondin-1 (TSP1) and connective tissue growth factor (CTGF) (Dews et al., 2006); miR-378 overexpression in glioblastoma cell line U87 enhanced angiogenesis and tumor growth through its targeting of tumor suppressor proteins SUFU and FUS-1 (Barakat et al., 2007); miR-296 is highly expressed in primary human brain microvascular endothelial cells and contributes to angiogenesis by directly targeting the hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) mRNA, leading to decreased levels of HGS and thereby reducing HGS-mediated degradation of the growth factor receptors VEGFR2 and PDGFR-b (Gabriely et al., 2008). Also in the regulation of the metastatic process miRNAs can be divided into two categories: prometastatic (such as miR-340, miR-92a, miR-10b, miR- miRNAs in body fluids as tumor biomarkers in hematological malignancies Diagnostic biomarkers Higher levels of circulating miR-21, -155 and -210 have been described in patients affected by diffuse large B-cell lymphoma (DLBCL), compared to controls (Lawrie, 2008). Interestingly, the same group had previously shown that the expression of miR-155 in primary DLBCLs distinguishes between the activated B-cell phenotype (ABC) (higher expression of miR155), than in the germinal center B-cell-like phenotype (GCB) (lower expression of miR-155) (Chen and Meister, 2005; Lawrie, 2007). Since, the 5-year survival rates of the ABC and the GCB subtypes of DLBCL are 30% and 59%, respectively (Kovanen et al., 2003), miR-155 expression in DLBCL has a prognostic value. A correlation between miR-155 and NFkB expression was found in DLBCL cell lines and patients (Abu-Elneel et al., 2008). In addition to miR155, high levels of miR-21 and miR-221 are also associated with ABC-DLBCL and severe prognosis (de Yebenes and Ramiro, 2010). It would be interesting to investigate whether the expression of circulating miR155 correlates with the expression of this miRNA in primary DLBCL, since it would indicate that miR-155 is a diagnostic biomarkers not only to put the diagnosis of DLBCL, but also of subtype of DLBCL. Prognostic biomarkers In DLBCL, increased serum levels of miR-21 are associated with a longer relapse-free survival (Lawrie, 2008), indicating that circulating miR-21 harbors prognostic implications in patients affected by DLBCL. Overall, miRNAs can be detected in body fluids and increasing evidence shows that their expression in these fluids allows the diagnosis of cancer histotype and, in some cases histologic subtype. Finally, specific signatures of de-regulated miRNAs in body fluids harbor prognostic implications. These discoveries cast a new light on the translational implications of research in the miRNA field, by suggesting that these noncoding RNAs could be detected non-invasively and provide key diagnostic and prognostic clinical information. miRNAs in invasion, angiogenesis and metastasis In the last few years several studies have pointed out a critical role of miRNAs in tumor angiogenesis and metastasis. By regulating these processes miRNAs have emerged as crucial players, thus allowing primary tumor cells to invade adjacent tissues and reach through Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 61 MicroRNAs and Cancer Calore F, Fabbri M hepatocellular carcinoma miR-34a is also downregulated (Li et al., 2009) and its expression is inversely correlated with that of the receptor for the hepatocyte growth factor c-MET (Leelawat et al., 2006), involved in cell invasion and metastasis. In their study the Authors demonstrated that miR-34a targets cMET when ectopically expressed in Hep-G2 cells and observed reduced cell scattering, migration and invasion. Crk (v-crk sarcoma virus CT 10 oncogene homolog) is a protein that regulates cell motility, differentiation and adhesion (Kobashigawa et al., 2007). High expression levels of this protein are found in several human tumors such as breast, ovarian, lung, brain, stomach and chondrosarcoma (Wang et al., 2007) and knock down of Crk decreases cell migration and invasion (Rodrigues et al., 2005; Wang et al., 2007). Crawford et al. showed that Crk is a functional target of miR-126 in NSCLC tumors and that overexpression of miR-126 induces a decrease in adhesion, migration and invasion (Crawford et al., 2008). Finally, the list of anti-metastatic miRNAs includes miR-206 and miR-335. In a manuscript published in 2008 Tavazoie and coworkers took under consideration a set of miRNAs whose expression was lost in human breast cancer cells (Tavazoie et al., 2008). Among these they considered miR-206 and miR-335. By restoring their expression through retroviral transduction they found that the ability of these cells to migrate to the lung was lost. MiR-335 exerts its antimetastatic role by targeting PTPRN2 (receptor-type tyrosine protein phosphatase) (Varadi et al., 2005), MERTK (the c-Mer tyrosine kinase) (Graham et al., 1995), SOX4 (SRY-box containing transcription factor), the progenitor cell transcription factor (van de Wetering et al., 1993; Hoser et al., 2007) and TNC (tenascin C) (Ilunga et al., 2004), which is an extracellular component of the matrix. 373/520c) or anti-metastatic (such as miR-101, miR34a, miR-126, miR-148a, miR-335) ones. In breast cancer reduced miR-340 expression is associate with tumor cell migration, invasion and poor prognosis (Dong et al., 2011). Of the six mature miRNAs produced by the miR-1792a cluster, miR-92a is involved in the metastatization process. It has been reported that miR-92a is highly expressed in tumor tissue from ESCC (Esophageal Squamous Cell Carcinoma) patients (Cai et al., 2008). Chen et al. verified whether there is a correlation between the relative expression of miR-92a in tumor and normal tissues and lymph node metastasis in ESCC patients. Not only they found that miR-92a promotes ESCC cell migration and invasion through the inhibition (by direct targeting) of CDH1, which is known to mediate cell-to-cell adhesion, but also that ESCC patients with up-regulated miR-92a are prone to lymph node metastasis and poor prognosis (Bao et al., 2011). In 2007, Ma et al. reported that miR-10b is highly expressed in metastatic breast cancer cells, when compared with non-metastatic cells. However, when overexpressed in the latter it promotes robust invasion and metastasis. Induced by the transcription factor Twist, miR-10 inhibits the translation of the messenger RNA encoding HOXD10 (homeobox D10), thus increasing the expression of the pro-metastatic gene RHOC and leading to tumor invasion and metastasis (Derby et al., 2007). Through the transduction of a non-metastatic breast cancer cell line with a miRNA expression library Huang et al. studied which miRNAs could allow the cells to migrate. MiR-373 and miR-520c were found to promote cell invasion and metastasis both in vitro and in vivo through the inhibition of the expression of CD44, a protein involved in cell adhesion (Abdurakhmonov et al., 2008). As previously reported, miRNAs are known also to have an anti-metastatic role. One of them is miR-101, whose expression decreases during prostate cancer progression, as depicted by Varambally et al. (Varambally et al., 2008). The authors showed that during this process there's a negative correlation between the expression of miR-101 and EZH2, a mammalian histone methyltransferase overexpressed in solid tumors (Varambally et al., 2002) and involved in the epigenetic silencing (Yu et al., 2007; Cao et al., 2008) of genes responsible for tumor invasion and metastasis. By performing experiments based on computational analysis the authors showed also that miR-101 targets EZH2. Loss of miR-101, paralleled by increased levels of EZH2 in the tumor, leads to dysregulation of epigenetic pathways and cancer progression. Another miRNA typically downregulated in tumors (colorectal cancer (Tazawa et al., 2007), pancreatic cancer (Chang et al., 2007), and neuroblastoma (Welch et al., 2007)) is miR-34a. Li et al. observed that in Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Therapeutic implications of miRNAs in oncology The involvement of miRNAs in different aspects of human carcinogenesis, such as cell proliferation, apoptosis, differentiation, angiogenesis, motility and metastasis, has raised the question whether reverting these aberrations of the miRNome can be effectively used for therapeutic purposes. Preclinical data encourage this hypothesis and provide the biological rationale for clinical studies in this direction. Reexpression of miRNAs down-regulated in cancer (e.g. miR-15a and miR-16 in BCL2 positive CLL) and/or silencing of miRNAs up-regulated in the tumor (e.g. miR-155 in lung cancer) may lead to cancer cell apoptosis and exert a therapeutic effect. Before this becomes a reality in patients though, several issues need to be solved. First, there is a need to know the full spectrum of targets and effects that a given miRNA has on a given genome. It has been estimated that a single miRNA cluster (namely, the miR-15a/16-1 cluster) is 62 MicroRNAs and Cancer Calore F, Fabbri M able to affect, directly and indirectly, the expression of about 14% of the whole human genome (Calin et al., 2008). Also it is clear that each miRNA is able to target both OGs and TSGs, and that the phenotype induced by the external manipulation of a miRNA is the result of this combined targeting effect on several genes. Therefore, one of the goals of the preclinical research is to fully clarify this aspect before any clinical application can even be taken into consideration. Secondly, it needs to be established how can we reach a tumor-specific delivery of the miRNAs of interest? This question is more general, and involves the whole field of gene therapy, being not limited to the research on miRNAs. The advent of nanoparticles, able to target tumor-specific antigens hopefully will address this concern and allow tumor specificity. 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Other aspects of miRNA research are still under development, such as their role as molecular biomarkers (the published studies still suffer in most cases from a limited number of patients, which questions the statistical power of certain results), the identification of the full spectrum of targets of a given miRNA (in particular, there is a need to critically interpret the plethora of the identified targets in light of the specific genome in which the effect is observed, and in relation to the other identified and validated targets of that same miRNA), and their interaction with the existing treatments (the number of published studies on this regard is still relatively small to allow any safe conclusion). Nonetheless, despite there seems to be still a lot of work ahead, it is promising that in such a relatively small amont of time, from the discovery of their involvement in human cancer, till today so much has been discovered about miRNAs and cancer. 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Meat Sci. 2011 Mar;87(3):299303 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 69 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Case Report Section Paper co-edited with the European LeukemiaNet Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis Francesca Cambosu, Giuseppina Fogu, Paola Maria Campus, Claudio Fozza, Luigi Podda, Andrea Montella, Maurizio Longinotti Clinical Genetics, Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B 07100 Sassari, Italy (FC, GF, AM); Azienda Ospedaliero-Universitaria Sassari, Italy (PMC, CF, LP, AM, ML); Institute of Hematology, University of Sassari, Italy (CF, LP, ML) Published in Atlas Database: September 2011 Online updated version : http://AtlasGeneticsOncology.org/Reports/der918p10q10CambosuID100057.html DOI: 10.4267/2042/47273 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Diagnosis Polycythemia vera. Myelofibrosis: hypocellular bone marrow with marked increase in reticulin fibres. AML M2. Clinics Age and sex 66 years old male patient. Previous history No preleukemia. No previous malignancy. No inborn condition of note. Organomegaly Hepatomegaly (enlarged liver (+ 20 cm)), splenomegaly, no enlarged lymph nodes , no central nervous system involvement. Survival Date of diagnosis: 01-1980 Treatment Bleeding therapy and acethylsalicylic acid. 2005 -2008: Etanercept (anti-TNF alpha). 2007: Hydroxyurea. Sept. 2008: Splenectomy. Feb. 2008: Pomalidomide, suspended after 1 month because of a severe neutropeny. Feb 2009: Bone Marrow allograft. Complete remission : no (March-November 2009: complete hematological remission; molecular remission not reached (JAK-2 positivity in June 2009)) Treatment related death : no Relapse : no Status: Death. Last follow up: 11-2010 (due to gastrointestinal hemorrhage). Survival: nearly 30 years. Blood WBC : 46 X 109/l HB : 8.5 g/dl Platelets : 239 X 109/l Blasts : 15% Bone marrow : 25% Cyto-Pathology Classification Karyotype Cytology: NA Immunophenotype: NA Rearranged Ig Tcr: NA Pathology: NA Electron microscopy: NA Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Sample: Bone marrow biopsy in Dec. 2008 Culture time: 24 and 48 h. Banding: Cytogenetic analysis performed in QFQ banding; band level: 400. Results 46,XY, +9,der(9;18)(p10;q10) in 25/25 cells scored. 70 Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis Cambosu F, et al. Comments Probes: whole-chromosome painting probes (wcp) and centromeric (CEP) probes of chromosomes 9 (9p11-q11 alpha satellite DNA) and 18 (D18Z1) (Abbott Molecular/Vysis). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 71 Polycythemia Vera (PV) is a clonal myeloproliferative disorder characterized by excessive erythrocyte production, which may evolve into myelofibrosis and acute myeloid leukemia. Transformation to myelofibrosis occurs in 15-20% of cases and leukemic transformation in 5-10% of patients. The median survival time is 8-11 years and the median age at diagnosis is over 60 years. Normal karyotype is present at diagnosis in the majority of patients, while during transformation several acquired chromosome anomalies are present as trisomy 9 and gains in 9p. The activating JAK2 V617F mutation, present in the majority of patients with PV, seems to have a primary role in the pathogenesis of myeloproliferative neoplasms. The JAK2 gene maps to 9p24, so patients carrying gains of 9p have an extra copy of the gene, in its normal or mutated form, leading to a gain of function. The rearrangement here reported, der(9;18)(p10;q10), is rarely detected in patients with PV, myelofibrosis, essential thrombocythemia and therapy-related AML. Some authors suggest that the simultaneous presence of both JAK2 V617F mutation and this rearrangement could define a subgroup of PV patients with the proliferative phenotype of the disease, at high risk of transformation into postpolycythemic myelofibrosis and potentially acute myeloid leukemia. We describe a new case of der(9;18)(p10;q10) detected in a patient with AML evolved from post-polycythemic myelofibrosis. The patient was diagnosed with PV in 1980 and died in 2010. He was in good health for several years after diagnosis with bleeding treatment and low dose aspirin, then he showed a progressive worsening of anemia with liver enlargement and splenomegaly. In February 2008 the diagnosis was of myelofibrosis post PV in progression. In December 2008, when the leukemic transformation was evident, the cytogenetic analysis on bone marrow aspirate found the unbalanced translocation leading to der(9;18)(p10;q10), with trisomy of the short arms of chromosome 9 and monosomy of the short arms of chromosome 18. FISH experiments with specific alphoid centromeric probes for chromosome 9 and 18 showed both positive signals on the der(9). Subsequent molecular analysis detected the presence of the JAK2 V617F mutation. The patient here reported had a classical evolution of the disease, after a very long polycythemic phase with a noteworthy survival time likely correlated to the young age of the patient when PV occurred. Because of the absence of cytogenetic results at diagnosis and during the polycythemic phase, we cannot fully evaluate the significance of der(9;18)(p10;q10) in the natural history of the disease before its evolution. Future reports could make clear this not negligible aspect. Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis Ohyashiki K, Kodama A, Ohyashiki JH. Recurrent der(9;18) in essential thrombocythemia with JAK2 V617F is highly linked to myelofibrosis development. Cancer Genet Cytogenet. 2008 Oct;186(1):6-11 References Chen Z, Notohamiprodjo M, Guan XY, Paietta E, Blackwell S, Stout K, Turner A, Richkind K, Trent JM, Lamb A, Sandberg AA. Gain of 9p in the pathogenesis of polycythemia vera. Genes Chromosomes Cancer. 1998 Aug;22(4):321-4 Xu X, Chen X, Rauch EA, Johnson EB, Thompson KJ, Laffin JJS, Raca G, Kurtycz DF.. Unbalanced rearrangement der(9;18)(p10;q10) in a patient with polycythemia vera. Atlas Genet Cytogenet Oncol Haematol. April 2010. URL: http://AtlasGeneticsOncology.org/Genes/der0918XuID100044. html . 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 This article should be referenced as such: Bacher U, Haferlach T, Schoch C. Gain of 9p due to an unbalanced rearrangement der(9;18): a recurrent clonal abnormality in chronic myeloproliferative disorders. Cancer Genet Cytogenet. 2005 Jul 15;160(2):179-83 Cambosu F, Fogu G, Campus PM, Fozza C, Podda L, Montella A, Longinotti M. Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):70-72. Larsen TS, Hasselbalch HC, Pallisgaard N, Kerndrup GB. A der(18)t(9;18)(p13;p11) and a der(9;18)(p10;q10) in polycythemia vera associated with a hyperproliferative phenotype in transformation to postpolycythemic myelofibrosis. Cancer Genet Cytogenet. 2007 Jan 15;172(2):107-12 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) Cambosu F, et al. 72 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Educational Items Section Weird animal genomes and sex chromosome evolution Jenny Graves La Trobe University, Melbourne, Australia (JG) (Paper co-edited with the European Cytogeneticists Association) Published in Atlas Database: August 2011 Online updated version : http://AtlasGeneticsOncology.org/Educ/SexChromID30061EL.html DOI: 10.4267/2042/47274 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Lactation complex: big changes in milk composition between newborn and 3 months pouch young. Premmies? Control? There are 26 species of kangaroo. We chose the tammar wallaby as our model kangaroo. Small, easy to handle, most of the classic work on marsupial physiology is done on this species. Embryonic diapause: blastocyst goes into suspended animation for up to 11 months. Premature birth of underdeveloped Young: limb, organ development still going on. Provides opportunities for observation and manipulation of development that are impossible in mouse. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 73 Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis Inter-island crosses like M. musculus x M. spretus because they are very different. - Lots of markers: microsatellite (variable numbers of repeats). - Have loads of phenotypic differences including in reproductive characters like diapauses. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 74 Cambosu F, et al. Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis Mono and tammar differ by about 10 interchromosomal rearrangements. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 75 Cambosu F, et al. Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 76 Cambosu F, et al. Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis Cambosu F, et al. Degeneration of the sex-specific element (Y or W) from an original autosome, with examples of animal species which exhibit this level of differentiation. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 77 Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 78 Cambosu F, et al. Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 79 Cambosu F, et al. Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 80 Cambosu F, et al. Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 81 Cambosu F, et al. Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis Nice examples of neofunctionalization (SRY, RBMY) and subfunctionalization. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 82 Cambosu F, et al. Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis Cambosu F, et al. This article should be referenced as such: Graves J. Weird animal genomes and sex chromosome evolution. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1):73-83. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 83 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. The Atlas publishes "cards", "deep insights", "case reports", and "educational items". 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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 Unbalanced rearrangement der(9;18)(p10;q10) and JAK2 V617F mutation in a patient with AML following post-polycythemic myelofibrosis Atlas Genet Cytogenet Oncol Haematol. 2012; 16(1) 85 Cambosu F, et al.