| First Author | Takai H | Year | 2002 |
| Journal | EMBO J | Volume | 21 |
| Issue | 19 | Pages | 5195-205 |
| PubMed ID | 12356735 | Mgi Jnum | J:88888 |
| Mgi Id | MGI:3037394 | Doi | 10.1093/emboj/cdf506 |
| Citation | Takai H, et al. (2002) Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. EMBO J 21(19):5195-205 |
| abstractText | The mammalian Chk2 kinase is thought to mediate ATM-dependent signaling in response to DNA damage. The physiological role of mammalian Chk2 has now been investigated by the generation of Chk2-deficient mice. Although Chk2(-/-) mice appeared normal, they were resistant to ionizing radiation (IR) as a result of the preservation of splenic lymphocytes. Thymocytes and neurons of the developing brain were also resistant to IR-induced apoptosis. The IR-induced G(1)/S cell cycle checkpoint, but not the G(2)/M or S phase checkpoints, was impaired in embryonic fibroblasts derived from Chk2(-/-) mice. IR-induced stabilization of p53 in Chk2(-/- )cells was 50-70% of that in wild-type cells. Caffeine further reduced p53 accumulation, suggesting the existence of an ATM/ATR-dependent but Chk2-independent pathway for p53 stabilization. In spite of p53 protein stabilization and phosphorylation of Ser23, p53-dependent transcriptional induction of target genes, such as p21 and Noxa, was not observed in Chk2(-/-) cells. Our results show that Chk2 plays a critical role in p53 function in response to IR by regulating its transcriptional activity as well as its stability. |
