Chk1 Suppresses a Caspase-2 Apoptotic Response to DNA Damage that Bypasses p53, Bcl-2, and Caspase-3

S. Sidi, T. Sanda, A.T. Hagen, C.A. Jette, R. Hoffmans, J. Pascual, J.P. Kanki, A.T. Look, R.D. Kennedy, A.A. D'Andrea, S. Imamura, S. Kishi, J.F. Amatruda, D.R. Green

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314 Citations (Scopus)

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 ?-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 ?-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. © 2008 Elsevier Inc. All rights reserved.
Original languageEnglish
Pages (from-to)864-877
Number of pages14
JournalCell
Volume133
Issue number5
DOIs
Publication statusPublished - 30 May 2008

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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    Sidi, S., Sanda, T., Hagen, A. T., Jette, C. A., Hoffmans, R., Pascual, J., Kanki, J. P., Look, A. T., Kennedy, R. D., D'Andrea, A. A., Imamura, S., Kishi, S., Amatruda, J. F., & Green, D. R. (2008). Chk1 Suppresses a Caspase-2 Apoptotic Response to DNA Damage that Bypasses p53, Bcl-2, and Caspase-3. Cell, 133(5), 864-877. https://doi.org/10.1016/j.cell.2008.03.037