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Chk1 suppresses a caspase-2 apoptotic response to DNA damage that bypasses p53, Bcl-2, and caspase-3

Academic Article
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Overview

authors

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

publication date

  • May 2008

journal

  • Cell  Journal

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.

subject areas

  • Animals
  • Apoptosis
  • Caspase 2
  • Caspase 3
  • Cell Line, Tumor
  • DNA Damage
  • Embryo, Nonmammalian
  • Enzyme Inhibitors
  • Gamma Rays
  • Humans
  • Protein Kinases
  • Proto-Oncogene Proteins c-bcl-2
  • Signal Transduction
  • Tumor Suppressor Protein p53
  • Zebrafish
  • Zebrafish Proteins
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Identity

PubMed Central ID

  • PMC2719897

International Standard Serial Number (ISSN)

  • 0092-8674

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2008.03.037

PubMed ID

  • 18510930
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Additional Document Info

start page

  • 864

end page

  • 877

volume

  • 133

issue

  • 5

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