期刊
CANCER CELL
卷 11, 期 2, 页码 175-189出版社
CELL PRESS
DOI: 10.1016/j.ccr.2006.11.024
关键词
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资金
- NCI NIH HHS [CA112967, U54 CA112967, CA14051, U54 CA112967-050003] Funding Source: Medline
- NIEHS NIH HHS [ES002109, R01 ES015339-03, ES015339, R01 ES015339] Funding Source: Medline
- NIGMS NIH HHS [R01 GM060594-09, R01 GM060594, GM60594] Funding Source: Medline
In response to DNA damage, eukaryotic cells activate ATM-Chk2 and/or ATR-Chk1 to arrest the cell cycle and initiate DNA repair. We show that, in the absence of p53, cells depend on a third cell-cycle checkpoint pathway involving p38MAPK/MK2 for cell-cycle arrest and survival after DNA damage. MK2 depletion in p53-deficient cells, but not in p53 wild-type cells, caused abrogation of the Cdc25A-mediated S phase checkpoint after cisplatin exposure and loss of the Cdc25B-mediated G(2)/M checkpoint following doxorubicin treatment, resulting in mitotic catastrophe and pronounced regression of murine tumors in vivo. We show that the Chk1 inhibitor UCN-01 also potently inhibits MK2, suggesting that its clinical efficacy results from the simultaneous disruption of two critical checkpoint pathways in p53-defective cells.
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