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

S. Zhang, Y. Lin, Y. S. Kim, M. P. Hande, Z. G. Liu, H. M. Shen

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

Abstract

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 (H2O2)-induced nonapoptotic cell death. The main objective of this study is to further elucidate the molecular mechanisms downstream of JNK1 in H2O2- induced cell death. In this study, poly(ADP-ribose) polymerase-1 (PARP-1), a key DNA repair protein, was readily activated by H2O2 and inhibition of PARP-1 activation by either a pharmacological or genetic approach offered significant protection against H2O2-induced cell death. More importantly, H2O2-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 H2O2, 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 H2O2-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 H2O2-induced nonapoptotic cell death: JNK1 promotes a sustained PARP-1 activation via nuclear translocation, protein-protein interaction and PARP-1 phosphorylation.

Original languageEnglish (US)
Pages (from-to)1001-1010
Number of pages10
JournalCell Death and Differentiation
Volume14
Issue number5
DOIs
StatePublished - May 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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