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

• Published in: Cell death and differentiation Vol. 14; no. 5; pp. 1001 - 1010
• Main Authors: Zhang, S, Lin, Y, Kim, Y-S, Hande, M P, Liu, Z-G, Shen, H-M
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01-05-2007
• Subjects: Adenosine Triphosphate - deficiency; Animals; Anthracenes - pharmacology; Apoptosis; Cancer; Caspases - metabolism; Cell death; Cell Death - drug effects; Cell Nucleus - drug effects; Cell Nucleus - metabolism; DNA damage; DNA repair; Embryo, Mammalian - cytology; Embryo, Mammalian - drug effects; Embryo, Mammalian - enzymology; Enzyme Activation - drug effects; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - enzymology; Free radicals; Humans; Hydrogen peroxide; Hydrogen Peroxide - pharmacology; Kinases; Medical research; Medicine; Mice; Mitogen-Activated Protein Kinase 8 - metabolism; Morphology; Oxidative stress; Phosphorylation; Phosphorylation - drug effects; Physiology; Poly(ADP-ribose) Polymerases - metabolism; Protein Binding - drug effects; Protein Transport - drug effects; Proteins; Tumor necrosis factor-TNF; United States > US; Singapore
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/sj.cdd.4402088

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.