c-Jun N-terminal kinase mediates hydrogen peroxide-induced cell death via sustained poly(ADP-ribose) polymerase-1 activation

Cell Death Differ. 2007 May;14(5):1001-10. doi: 10.1038/sj.cdd.4402088. Epub 2007 Jan 12.


Reactive oxygen species (ROS) have been closely associated with both apoptotic and non-apoptotic/necrotic cell death. Our previous study has illustrated that c-Jun-N-terminal kinase 1 (JNK1) is the main executor in hydrogen peroxide (H(2)O(2))-induced nonapoptotic cell death. The main objective of this study is to further elucidate the molecular mechanisms downstream of JNK1 in H(2)O(2)-induced cell death. In this study, poly(ADP-ribose) polymerase-1 (PARP-1), a key DNA repair protein, was readily activated by H(2)O(2) and inhibition of PARP-1 activation by either a pharmacological or genetic approach offered significant protection against H(2)O(2)-induced cell death. More importantly, H(2)O(2)-mediated PARP-1 activation is subject to regulation by JNK1. Suppression of JNK1 activation by a chemical inhibitor or genetic deletion markedly suppressed the late-phase PARP-1 activation induced by H(2)O(2), suggesting that JNK1 contributes to the sustained activation of PARP-1. Such findings were supported by the temporal pattern of nuclear translocation of activated JNK and a direct protein-protein interaction between JNK1 and PARP-1 in H(2)O(2)-treated cells. Finally, in vitro kinase assay suggests that PARP-1 may serve as the direct phosphorylation target for JNK1. Taken together, data from our study reveal a novel underlying mechanism in H(2)O(2)-induced nonapoptotic cell death: JNK1 promotes a sustained PARP-1 activation via nuclear translocation, protein-protein interaction and PARP-1 phosphorylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / deficiency
  • Animals
  • Anthracenes / pharmacology
  • Caspases / metabolism
  • Cell Death / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / drug effects
  • Embryo, Mammalian / enzymology
  • Enzyme Activation / drug effects
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology
  • Humans
  • Hydrogen Peroxide / pharmacology*
  • Mice
  • Mitogen-Activated Protein Kinase 8 / metabolism*
  • Phosphorylation / drug effects
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Protein Binding / drug effects
  • Protein Transport / drug effects


  • Anthracenes
  • pyrazolanthrone
  • Adenosine Triphosphate
  • Hydrogen Peroxide
  • Poly(ADP-ribose) Polymerases
  • Mitogen-Activated Protein Kinase 8
  • Caspases