Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review CKS2 (CDC28 protein kinase regulatory subunit 2) Yongyou Zhang Case Western Reserve University, WRB-3101, 2103 Cornell Rd, Cleveland, OH 44106, USA (YZ) Published in Atlas Database: February 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/CKS2ID40093ch9q22.html DOI: 10.4267/2042/44906 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Description Identity The open reading frame encodes a 79 amino acid protein, with an estimated molecular weight of approximately 9860 Da. Other names: CKSHS2 HGNC (Hugo): CKS2 Location: 9q22.2 Note: There is no evidence that CKS2 gene has different transcript variant. Expression Basic level expression in all mammalian cells and aberrant expression in cancer cells. Localisation DNA/RNA Cytoplasm and nucleus. Function Transcription CKS2 protein binds to the catalytic subunit of the cyclin-dependent kinases and is essential for their biological function of cell cycle control. Especially, CKS2 is required for the first metaphase/anaphase transition of mammalian meiosis. The mice ablated of Cks2 are viable but sterile in both sexes. Sterility is due to failure of both male and female germ cells to progress from the first meiotic metaphase to anaphase. In cancer cells, CKS2 may protect the cells from apoptosis. mRNA is 627 bp. Homology Pseudogene The CKS2 protein is evolutionary conserved. Mammalian cells express two well-conserved CKS members, like the human CKS2 and CKS1B proteins. CKS2 and CKS1B may have redundant function in some context and have different functions in other context. The CKS2 protein is highly conserved cross species. Genomic organization of the CKS2 gene. Description Three exons, spans approximately 5.5 kb of genomic DNA in the centromere-to-telomere orientation. The translation initiation codon ATG is located in exon 1, and the stop codon in exon 3. 1 processed, non-expressed, pseudogene in human genome. Protein Note The Cks2 protein can form a special homohexamer structure. Six kinase subunits can bind the assembled hexamer, and therefore this Cks2 hexamer may participate in cell cycle control by acting as the hub for Cdk multimerization in vivo. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Mutations Note Mutation of glutamine for glutamate 63 (E63Q), 1100 CKS2 (CDC28 protein kinase regulatory subunit 2) Zhang Y disrupted the essential biological function of the protein and significantly reduced its ability to bind to cyclindependent kinases, but preserves protein structure and assembly. (Wiese et al., 2007). CKS2 was also showed to be higher in liver metastasis compared with primary colon cancer (Lin et al., 2007). Oncogenesis Amplification and overexpression of CKS2 were associated with liver metastasis and poor prognosis in colon cancer. CKS2 is required for germ cell to go past the first meiotic metaphase and enter anaphase. In cancer cell, overexpression of CKS2 can accelerate the cell cycles and promote the cell proliferation. Recently research showed that CKS2 may also be involved in apoptosis and metabolism since it can protect mitochondrial genome integrity via interaction with mitochondrial single-stranded DNA-binding protein. Study also showed CKS2 as a transcriptional target downregulated by the tumor suppressor p53. CKS2 expression was found to be repressed by p53 both at the mRNA and the protein levels, which may provide a mechanism that explain why CKS2 is upregulated in many types of cancer. All of these suggest that CKS2 alterations may have a significant biological role in the tumorigenesis in different tissue. The novel therapeutic strategy for cancer though may be developed via inhibiting the CKS2 activity. Therefore, disruption of CKS2-Cyclin Complex assembly or down-regulation of CKS2 expression may be used for cancer therapy. Implicated in Various cancers Note Emerging evidence showed that the expression of CKS2 is elevated in multiple cancers, including prostate cancer, breast cancer, gastric cancer, colorectal cancer, uterine cervical cancer, bladder cancer, nasopharyngeal carcinoma, melanoma, lymphoma, lung cancer, esophageal squamous cell carcinoma et al. The expression of CKS2 is correlated with poor survival rate of the patients of some cancers. Prognosis Overexpression of CKS2 has been reported to be associated with high aggressiveness and a poor prognosis in multiple cancers, including breast cancer, prostate cancer, colon cancer, hepatocellular carcinoma and meningiomas et al. Hepatocellular carcinoma (HCC) Note Expressions of CKS2 were significantly higher in HCC compared with the adjacent noncancerous tissues (including chronic hepatitis and cirrhosis) and normal liver tissues. Overexpression of CKS2 in HCC were closely associated with poor differentiation features (Shen et al., 2010). Esophageal squamous cell carcinoma Note Gene expression profiling of lymph node metastasis by oligomicroarray analysis and Real-time RT-PCR confirmed that CKS2 is unregulated in laser microdissection of esophageal squamous cell carcinoma compared with adjacent normal tissue (Uchikado et al., 2006). Gastric cancer Note CKS2 was showed to be significantly unregulated in gastric cancers. The high level of CKS2 was highly correlated with tumor differentiation and pathological grade of the tumor size, lymph node, and metastasis stage (Kang et al., 2009). Uterine cervical cancer Note CKS2 was showed significantly higher in node positive tumor compared with negative one. The CKS2 expression is correlated with metastatic phenotypes and progression free survival. (Lyng et al., 2006). Prostate cancer Note CKS2 were significantly unregulated in prostate tumors of human and animal models, as well as prostatic cancer cell lines. Forced expression of CKS2 in benign prostate tumor epithelial cells promoted cell population growth. Inhibition of CKS2 expression can induce programmed cell death and inhibit the tumorigenesis. (Lan et al., 2008). Over expression of CKS2 may linked with androgen-independent prostate cancer progression (Stanbrough et al., 2006). Bladder cancer Note Large-scale gene expression profiling and Real-Time RT-PCR confirmed that a the CKS2 expression is elevated in invasive bladder cancer compared with superficial cancer (Kawakami et al., 2006). Glioblastoma Note CKS2 was significantly up-regulated in primary glioblastomas compared with the non-neoplastic brain tissues (Scrideli et al., 2008). Colon cancer Note CKS2 was reported significantly overexpressed in microdissected invasive colon tumor cells compared with adjacent normal epithelial cells Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) Meningioma Note This microarray-based expression profiling study 1101 CKS2 (CDC28 protein kinase regulatory subunit 2) Zhang Y bladder cancer through genome-wide gene profiling. Oncol Rep. 2006 Sep;16(3):521-31 showed CKS2 is unregulated in atypical and anaplastic meningiomas compared with benign meningiomas (Fevre-Montange et al., 2009). Lyng H, Brøvig RS, Svendsrud DH, Holm R, Kaalhus O, Knutstad K, Oksefjell H, Sundfør K, Kristensen GB, Stokke T. Gene expressions and copy numbers associated with metastatic phenotypes of uterine cervical cancer. BMC Genomics. 2006 Oct 20;7:268 References Parge HE, Arvai AS, Murtari DJ, Reed SI, Tainer JA. Human CksHs2 atomic structure: a role for its hexameric assembly in cell cycle control. Science. 1993 Oct 15;262(5132):387-95 Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, Febbo PG, Balk SP. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006 Mar 1;66(5):2815-25 Demetrick DJ, Zhang H, Beach DH. Chromosomal mapping of the human genes CKS1 to 8q21 and CKS2 to 9q22. Cytogenet Cell Genet. 1996;73(3):250-4 Uchikado Y, Inoue H, Haraguchi N, Mimori K, Natsugoe S, Okumura H, Aikou T, Mori M. Gene expression profiling of lymph node metastasis by oligomicroarray analysis using laser microdissection in esophageal squamous cell carcinoma. Int J Oncol. 2006 Dec;29(6):1337-47 Pines J. Cell cycle: reaching for a role for the Cks proteins. Curr Biol. 1996 Nov 1;6(11):1399-402 Watson MH, Bourne Y, Arvai AS, Hickey MJ, Santiago A, Bernstein SL, Tainer JA, Reed SI. A mutation in the human cyclin-dependent kinase interacting protein, CksHs2, interferes with cyclin-dependent kinase binding and biological function, but preserves protein structure and assembly. J Mol Biol. 1996 Sep 6;261(5):646-57 Wong YF, Cheung TH, Tsao GS, Lo KW, Yim SF, Wang VW, Heung MM, Chan SC, Chan LK, Ho TW, Wong KW, Li C, Guo Y, Chung TK, Smith DI. Genome-wide gene expression profiling of cervical cancer in Hong Kong women by oligonucleotide microarray. Int J Cancer. 2006 May 15;118(10):2461-9 Egan EA, Solomon MJ. Cyclin-stimulated binding of Cks proteins to cyclin-dependent kinases. Mol Cell Biol. 1998 Jul;18(7):3659-67 Lin CY, Ström A, Li Kong S, Kietz S, Thomsen JS, Tee JB, Vega VB, Miller LD, Smeds J, Bergh J, Gustafsson JA, Liu ET. Inhibitory effects of estrogen receptor beta on specific hormone-responsive gene expression and association with disease outcome in primary breast cancer. Breast Cancer Res. 2007;9(2):R25 Urbanowicz-Kachnowicz I, Baghdassarian N, Nakache C, Gracia D, Mekki Y, Bryon PA, Ffrench M. ckshs expression is linked to cell proliferation in normal and malignant human lymphoid cells. Int J Cancer. 1999 Jul 2;82(1):98-104 Seeliger MA, Schymkowitz JW, Rousseau F, Wilkinson HR, Itzhaki LS. Folding and association of the human cell cycle regulatory proteins ckshs1 and ckshs2. Biochemistry. 2002 Jan 29;41(4):1202-10 Lin HM, Chatterjee A, Lin YH, Anjomshoaa A, Fukuzawa R, McCall JL, Reeve AE. Genome wide expression profiling identifies genes associated with colorectal liver metastasis. Oncol Rep. 2007 Jun;17(6):1541-9 Donovan PJ, Reed SI. Germline exclusion of Cks1 in the mouse reveals a metaphase I role for Cks proteins in male and female meiosis. Cell Cycle. 2003 Jul-Aug;2(4):275-6 Rother K, Dengl M, Lorenz J, Tschöp K, Kirschner R, Mössner J, Engeland K. Gene expression of cyclin-dependent kinase subunit Cks2 is repressed by the tumor suppressor p53 but not by the related proteins p63 or p73. FEBS Lett. 2007 Mar 20;581(6):1166-72 Lu X, Guo J, Hsieh TC. PC-SPES inhibits cell proliferation by modulating p21, cyclins D, E and B and multiple cell cyclerelated genes in prostate cancer cells. Cell Cycle. 2003 JanFeb;2(1):59-63 Wiese AH, Auer J, Lassmann S, Nährig J, Rosenberg R, Höfler H, Rüger R, Werner M. Identification of gene signatures for invasive colorectal tumor cells. Cancer Detect Prev. 2007;31(4):282-95 Seeliger MA, Breward SE, Itzhaki LS. Weak cooperativity in the core causes a switch in folding mechanism between two proteins of the cks family. J Mol Biol. 2003 Jan 3;325(1):189-99 Haaber J, Abildgaard N, Knudsen LM, Dahl IM, Lodahl M, Thomassen M, Kerndrup GB, Rasmussen T. Myeloma cell expression of 10 candidate genes for osteolytic bone disease. Only overexpression of DKK1 correlates with clinical bone involvement at diagnosis. Br J Haematol. 2008 Jan;140(1):2535 Spruck CH, de Miguel MP, Smith AP, Ryan A, Stein P, Schultz RM, Lincoln AJ, Donovan PJ, Reed SI. Requirement of Cks2 for the first metaphase/anaphase transition of mammalian meiosis. Science. 2003 Apr 25;300(5619):647-50 Li M, Lin YM, Hasegawa S, Shimokawa T, Murata K, Kameyama M, Ishikawa O, Katagiri T, Tsunoda T, Nakamura Y, Furukawa Y. Genes associated with liver metastasis of colon cancer, identified by genome-wide cDNA microarray. Int J Oncol. 2004 Feb;24(2):305-12 Lan Y, Zhang Y, Wang J, Lin C, Ittmann MM, Wang F. Aberrant expression of Cks1 and Cks2 contributes to prostate tumorigenesis by promoting proliferation and inhibiting programmed cell death. Int J Cancer. 2008 Aug 1;123(3):54351 de Wit NJ, Rijntjes J, Diepstra JH, van Kuppevelt TH, Weidle UH, Ruiter DJ, van Muijen GN. Analysis of differential gene expression in human melanocytic tumour lesions by custom made oligonucleotide arrays. Br J Cancer. 2005 Jun 20;92(12):2249-61 Martinsson-Ahlzén HS, Liberal V, Grünenfelder B, Chaves SR, Spruck CH, Reed SI. Cyclin-dependent kinase-associated proteins Cks1 and Cks2 are essential during early embryogenesis and for cell cycle progression in somatic cells. Mol Cell Biol. 2008 Sep;28(18):5698-709 Chow LS, Lam CW, Chan SY, Tsao SW, To KF, Tong SF, Hung WK, Dammann R, Huang DP, Lo KW. Identification of RASSF1A modulated genes in nasopharyngeal carcinoma. Oncogene. 2006 Jan 12;25(2):310-6 Scrideli CA, Carlotti CG Jr, Okamoto OK, Andrade VS, Cortez MA, Motta FJ, Lucio-Eterovic AK, Neder L, Rosemberg S, Oba-Shinjo SM, Marie SK, Tone LG. Gene expression profile analysis of primary glioblastomas and non-neoplastic brain tissue: identification of potential target genes by oligonucleotide microarray and real-time quantitative PCR. J Neurooncol. 2008 Jul;88(3):281-91 Kawakami K, Enokida H, Tachiwada T, Gotanda T, Tsuneyoshi K, Kubo H, Nishiyama K, Takiguchi M, Nakagawa M, Seki N. Identification of differentially expressed genes in human Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) expression 1102 CKS2 (CDC28 protein kinase regulatory subunit 2) Zhang Y Fèvre-Montange M, Champier J, Durand A, Wierinckx A, Honnorat J, Guyotat J, Jouvet A. Microarray gene expression profiling in meningiomas: differential expression according to grade or histopathological subtype. Int J Oncol. 2009 Dec;35(6):1395-407 treatment in breast cancer. J Steroid Biochem Mol Biol. 2010 Feb 28;118(4-5):273-6 Radulovic M, Crane E, Crawford M, Godovac-Zimmermann J, Yu VP. CKS proteins protect mitochondrial genome integrity by interacting with mitochondrial single-stranded DNA-binding protein. Mol Cell Proteomics. 2010 Jan;9(1):145-52 Kang MA, Kim JT, Kim JH, Kim SY, Kim YH, Yeom YI, Lee Y, Lee HG. Upregulation of the cycline kinase subunit CKS2 increases cell proliferation rate in gastric cancer. J Cancer Res Clin Oncol. 2009 Jun;135(6):761-9 Shen DY, Fang ZX, You P, Liu PG, Wang F, Huang CL, Yao XB, Chen ZX, Zhang ZY. Clinical significance and expression of cyclin kinase subunits 1 and 2 in hepatocellular carcinoma. Liver Int. 2010 Jan;30(1):119-25 Wang F, Kuang Y, Salem N, Anderson PW, Lee Z. Crossspecies hybridization of woodchuck hepatitis viral infectioninduced woodchuck hepatocellular carcinoma using human, rat and mouse oligonucleotide microarrays. J Gastroenterol Hepatol. 2009 Apr;24(4):605-17 This article should be referenced as such: Zhang Y. CKS2 (CDC28 protein kinase regulatory subunit 2). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12):11001103. Miller WR. Clinical, pathological, proliferative and molecular responses associated with neoadjuvant aromatase inhibitor Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12) 1103