Abstract:
:Evasion of DNA damage-induced cell death, via mutation of the p53 tumor suppressor or overexpression of prosurvival Bcl-2 family proteins, is a key step toward malignant transformation and therapeutic resistance. We report that depletion or acute inhibition of checkpoint kinase 1 (Chk1) is sufficient to restore gamma-radiation-induced apoptosis in p53 mutant zebrafish embryos. Surprisingly, caspase-3 is not activated prior to DNA fragmentation, in contrast to classical intrinsic or extrinsic apoptosis. Rather, an alternative apoptotic program is engaged that cell autonomously requires atm (ataxia telangiectasia mutated), atr (ATM and Rad3-related) and caspase-2, and is not affected by p53 loss or overexpression of bcl-2/xl. Similarly, Chk1 inhibitor-treated human tumor cells hyperactivate ATM, ATR, and caspase-2 after gamma-radiation and trigger a caspase-2-dependent apoptotic program that bypasses p53 deficiency and excess Bcl-2. The evolutionarily conserved "Chk1-suppressed" pathway defines a novel apoptotic process, whose responsiveness to Chk1 inhibitors and insensitivity to p53 and BCL2 alterations have important implications for cancer therapy.
journal_name
Celljournal_title
Cellauthors
Sidi S,Sanda T,Kennedy RD,Hagen AT,Jette CA,Hoffmans R,Pascual J,Imamura S,Kishi S,Amatruda JF,Kanki JP,Green DR,D'Andrea AA,Look ATdoi
10.1016/j.cell.2008.03.037subject
Has Abstractpub_date
2008-05-30 00:00:00pages
864-77issue
5eissn
0092-8674issn
1097-4172pii
S0092-8674(08)00502-3journal_volume
133pub_type
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