Friday 26 September 2003
CHK2 is an important multifunctional player in the DNA-damage response signalling pathway. Parallel studies of the human CHEK2 gene have also highlighted its role as a candidate multiorgan tumour susceptibility gene rather than a highly penetrant predisposition gene for Li-Fraumeni syndrome.
The cell cycle checkpoint kinase CHEK2 is a protein kinase activated in response to DNA damage, is involved in cell cycle arrest. CHEK2 is the upstream regulator of p53 in the DNA-damage-signaling pathway.
CHK2 is mainly activated by DNA-strand-breaking agents such as ionizing radiation and topoisomerase inhibitors through the ATM-dependent pathway.
Other checkpoint proteins, such as 53BP1, MDC1 and the MRE11-RAD50-NBS1 complex, might modulate CHK2 activation. The role of CHK2 in checkpoints is not totally clear, although it has been shown to phosphorylate CDC25A in vitro, which inhibits its activity.
The role of CHK2 in DNA-damage-induced apoptosis is better established. It operates through both p53-dependent and p53-independent - through PML and E2F - pathways.
Pifithrin- can block p53-dependent transcription and apoptosis, and has been used as a tool to validate the p53-dependent pathway as a radio/chemosensitization target. CHK2 has also been shown to phosphorylate the BRCA1 protein and might modulate the role of BRCA1 in DNA repair.
germline mutations in tumor predisposing syndromes
- germline mutations in the Li-fraumeni syndrome (MIM.151623)
- 4.8% germline CHEK2 mutations in protate carcinoma patients (#12533788#)
- germline CHEK2 genetic variant in some familial breast cancers (#12094328#)
- CHEK2*1100delC variant of the cell cycle checkpoint kinase CHEK2 gene was present in 18% of 55 families with hereditary breast and colorectal cancer (HBCC) as compared with 4% in controls (#12690581#)
somatic mutations in numerous solid tumors. Exemples:
- prostatic carcinomas
Antoni L, Sodha N, Collins I, Garrett MD. CHK2 kinase: cancer susceptibility and cancer therapy - two sides of the same coin? Nat Rev Cancer. 2007 Dec;7(12):925-36. PMID: #18004398#
Bartek J, Lukas J. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell. 2003 May;3(5):421-9. PMID: #12781359#
Haruki N, Saito H, Tatematsu Y, Konishi H, Harano T, Masuda A, Osada H, Fujii Y, Takahashi T. Histological type-selective, tumor-predominant expression of a novel CHK1 isoform and infrequent in vivo somatic CHK2 mutation in small cell lung cancer. Cancer Res. 2000 Sep 1;60(17):4689-92. PMID: #10987268#