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07-SEPTEMBER-2008 03:17:44 - CHEK2 CHK2 checkpoint homolog S. pombe PDB rendering based on 1gxc. Available structures: 1gxc, 2cn5, 2cn8 Identifiers Symbols CHEK2; CDS1; CHK2; HuCds1; LFS2; PP1425; RAD53 External IDs OMIM: 604373 MGI: 1355321 HomoloGene: 38289 EC number 2.7.1.37 Gene ontology Molecular function: nucleotide binding magnesium ion binding protein serine/threonine kinase activity protein binding ATP binding transferase activity Cellular component: nucleus Biological process: DNA damage checkpoint protein amino acid phosphorylation response to DNA damage stimulus cell cycle RNA expression pattern More reference expression data Orthologs Human Mouse Entrez 11200 50883 Ensembl ENSG00000183765 ENSMUSG00000029521 Uniprot O96017 Q543W6 Refseq NM_001005735 mRNA NP_001005735 protein NM_016681 mRNA NP_057890 protein Location Chr 22: 27.41 - 27.47 Mb Chr 5: 111.08 - 111.11 Mb Pubmed search 1 2 CHEK2 is the official symbol for the human gene CHK2 checkpoint homolog. It is located on the long q arm of chromosome 22.123 Contents 1 Function 2 Related conditions 2.1 Breast cancer 2.2 Li-Fraumeni syndrome 3 References 4 Further reading 5 External links Function The protein encoded by this gene, CHK2 a protein kinase that is activated in response to DNA damage and is involved in cell cycle arrest.1 In response to DNA damage and replication blocks, cell cycle progression is halted through the control of cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1.4 In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage.56 Related conditions A mutation in CHEK2 gene results in decreased DNA-repair, or inability of the cell to undergo apoptosis when it ought to have done so. Thus, a mutation leads to an increased susceptibility to cancer. The following conditions are examples of such cancers. Breast cancer A deletion-mutation at position 1100 of the CHEK2 gene is associated with an increased risk of breast cancer, particularly in the European population. In women of Northern an Eastern European descent CHEK21100delC carrier status confers a 2-3 fold risk of breast cancer. In this ethnic group, women with a familial history of breast cancer have a 4.8 fold risk of breast cancer equal to a life time risk of breast cancer of 37%.7 Li-Fraumeni syndrome The CHEK21100delC mutation was originally associated with the Li-Fraumeni syndrome,8 however the relative high prevalence of the mutation in the general population 0.5% has made this association unlikely.9 References ^ a b Matsuoka S, Huang M, Elledge SJ December 1998. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science journal 282 5395: 1893-7. doi:10.1126/science.282.5395.1893. PMID 9836640. ^ Blasina A, de Weyer IV, Laus MC, Luyten WH, Parker AE, McGowan CH January 1999. A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase. Curr. Biol. 9 1: 1-10. doi:10.1016/S0960-98229980041-4. PMID 9889122. ^ Chaturvedi P, Eng WK, Zhu Y, Mattern MR, Mishra R, Hurle MR, Zhang X, Annan RS, Lu Q, Faucette LF, Scott GF, Li X, Carr SA, Johnson RK, Winkler JD, Zhou BB July 1999. Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Oncogene 18 28: 4047-54. doi:10.1038/sj.onc.1202925. PMID 10435585. ^ Chehab NH, Malikzay A, Appel M, Halazonetis TD February 2000. Chk2/hCds1 functions as a DNA damage checkpoint in G1 by stabilizing p53. Genes Dev. 14 3: 278-88. doi:10.1101/gad.14.3.278. PMID 10673500. ^ Lee JS, Collins KM, Brown AL, Lee CH, Chung JH March 2000. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404 6774: 201-4. doi:10.1038/35004614. PMID 10724175. ^ Entrez Gene: CHEK2 CHK2 checkpoint homolog S. pombe. ^ Meijers-Heijboer H, van den Ouweland A, Klijn J, et al May 2002. Low-penetrance susceptibility to breast cancer due to CHEK21100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat. Genet. 31 1: 55-9. doi:10.1038/ng879. PMID 11967536. ^ Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DC, Shannon KE, Lubratovich M, Verselis SJ, Isselbacher KJ, Fraumeni JF, Birch JM, Li FP, Garber JE, Haber DA December 1999. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science journal 286 5449: 2528-31. doi:10.1126/science.286.5449.2528. PMID 10617473. ^ Evans DG, Birch JM, Narod SA January 2008. Is CHEK2 a cause of the Li-Fraumeni syndrome?. J. Med. Genet. 45 1: 63-4. doi:10.1136/jmg.2007.054700. PMID 18178638. Further reading Caspari T 2000. How to activate p53.. Curr. Biol. 10 8: R315-7. PMID 10801407. McGowan CH 2002. Checking in on Cds1 Chk2: A checkpoint kinase and tumor suppressor.. Bioessays 24 6: 502-11. doi:10.1002/bies.10101. PMID 12111733. Honrado E, Osorio A, Palacios J, Benitez J 2006. Pathology and gene expression of herary breast tumors associated with BRCA1, BRCA2 and CHEK2 gene mutations.. Oncogene 25 43: 5837-45. doi:10.1038/sj.onc.1209875. PMID 16998498. Nevanlinna H, Bartek J 2006. The CHEK2 gene and inherited breast cancer susceptibility.. Oncogene 25 43: 5912-9. doi:10.1038/sj.onc.1209877. PMID 16998506. Peng CY, Graves PR, Thoma RS, et al. 1997. Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216.. Science 277 5331: 1501-5. PMID 9278512. Lykidis A, Jackson PD, Rock CO, Jackowski S 1998. The role of CDP-diacylglycerol synthetase and phosphatidylinositol synthase activity levels in the regulation of cellular phosphatidylinositol content.. J. Biol. Chem. 272 52: 33402-9. PMID 9407135. Lindsay HD, Griffiths DJ, Edwards RJ, et al. 1998. S-phase-specific activation of Cds1 kinase defines a subpathway of the checkpoint response in Schizosaccharomyces pombe.. Genes Dev. 12 3: 382-95. PMID 9450932. Matsuoka S, Huang M, Elledge SJ 1998. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.. Science 282 5395: 1893-7. PMID 9836640. Martinho RG, Lindsay HD, Flaggs G, et al. 1999. Analysis of Rad3 and Chk1 protein kinases defines different checkpoint responses.. EMBO J. 17 24: 7239-49. doi:10.1093/emboj/17.24.7239. PMID 9857181. Blasina A, de Weyer IV, Laus MC, et al. 1999. A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase.. Curr. Biol. 9 1: 1-10. PMID 9889122. Brown AL, Lee CH, Schwarz JK, et al. 1999. A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage.. Proc. Natl. Acad. Sci. U.S.A. 96 7: 3745-50. PMID 10097108. Chaturvedi P, Eng WK, Zhu Y, et al. 1999. Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway.. Oncogene 18 28: 4047-54. doi:10.1038/sj.onc.1202925. PMID 10435585. Ouyang B, Li W, Pan H, et al. 1999. The physical association and phosphorylation of Cdc25C protein phosphatase by Prk.. Oncogene 18 44: 6029-36. doi:10.1038/sj.onc.1202983. PMID 10557092. Dunham I, Shimizu N, Roe BA, et al. 1999. The DNA sequence of human chromosome 22.. Nature 402 6761: 489-95. doi:10.1038/990031. PMID 10591208. Bell DW, Varley JM, Szydlo TE, et al. 2000. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.. Science 286 5449: 2528-31. PMID 10617473. Chehab NH, Malikzay A, Appel M, Halazonetis TD 2000. Chk2/hCds1 functions as a DNA damage checkpoint in G1 by stabilizing p53.. Genes Dev. 14 3: 278-88. PMID 10673500. Hirao A, Kong YY, Matsuoka S, et al. 2000. DNA damage-induced activation of p53 by the checkpoint kinase Chk2.. Science 287 5459: 1824-7. PMID 10710310. Lee JS, Collins KM, Brown AL, et al. 2000. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response.. Nature 404 6774: 201-4. doi:10.1038/35004614. PMID 10724175. Zhou BB, Chaturvedi P, Spring K, et al. 2000. Caffeine abolishes the mammalian G2/M DNA damage checkpoint by inhibiting ataxia-telangiectasia-mutated kinase activity.. J. Biol. Chem. 275 14: 10342-8. PMID 10744722. External links Educational resources Gene Reviews Gene Tests MeSH CHEK2+protein,+human This article incorporates text from the United States National Library of Medicine, which is in the public domain. v d e Tumor suppressor genes/proteins Cell membrane/cytosol Neurofibromin 1 - Neurofibromin 2/Merlin - APC - PTEN Mitochondria SDHB - SDHD Nucleus pRb - p16 - p53 - BRCA1 - BRCA2 - Cell cycle CHEK2, p14arf, p21, p27, p57, p73 Other/ungrouped Maspin - VHL Retrieved from http://en..org/wiki/CHEK2 Categories: Genes on chromosome 22 | Human proteins Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Polski This page was last modified on 24 August 2008, at 09:48
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