c-Jun N-terminal kinase mediates hydrogen peroxide-induced cell death via sustained poly(ADP-ribose) polymerase-1 activation
c-Jun N-terminal kinase mediates hydrogen peroxide-induced cell death via sustained poly(ADP-ribose) polymerase-1 activation
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DOI：
10.1038/sj.cdd.4402088
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发表时间：
2007-05-01
影响因子：
12.4
通讯作者：
Shen, H-M
中科院分区：
文献类型：
--
作者：
Zhang, S.;Lin, Y.;Shen, H-M
活性氧（ROS）与细胞凋亡和非凋亡/坏死性细胞死亡密切相关。我们前期的研究表明，JNK 1是过氧化氢（H2 O2）诱导的非凋亡性细胞死亡的主要执行者。本研究的主要目的是进一步阐明JNK 1下游的分子机制在过氧化氢诱导的细胞死亡。在这项研究中，聚（ADP-核糖）聚合酶-1（PARP- 1），一种关键的DNA修复蛋白，很容易被H2 O2激活，通过药理学或遗传学方法抑制PARP- 1的激活，可以显著保护H2 O2诱导的细胞死亡。更重要的是，H2 O2介导的PARP- 1活化受JNK 1的调节。通过化学抑制剂或基因缺失抑制JNK 1活化显著抑制了H2 O2诱导的晚期PARP- 1活化，表明JNK 1有助于PARP- 1的持续活化。这些发现得到了激活的JNK的核转位的时间模式和H2 O2处理的细胞中JNK 1和PARP- 1之间的直接蛋白质-蛋白质相互作用的支持。最后，体外激酶试验表明，PARP- 1可能作为JNK 1的直接磷酸化靶点。总之，我们的研究数据揭示了H2 O2诱导的非凋亡性细胞死亡的一种新的潜在机制：JNK 1通过核转位、蛋白-蛋白相互作用和PARP- 1磷酸化促进持续的PARP- 1活化。
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.