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

Samuel Sidi, Takaomi Sanda, Richard D. Kennedy, Andreas T. Hagen, Cicely A. Jette, Raymond Hoffmans, Jennifer Pascual, Shintaro Imamura, Shuji Kishi, James F. Amatruda, John P. Kanki, Douglas R. Green, Alan A. D'Andrea, A. Thomas Look

Research output: Contribution to journalArticle

245 Scopus citations

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 γ-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 γ-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.

Original languageEnglish (US)
Pages (from-to)864-877
Number of pages14
JournalCell
Volume133
Issue number5
DOIs
StatePublished - May 30 2008

Keywords

  • CELLBIO
  • CELLCYCLE
  • SIGNALING

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

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