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J. Biol. Chem., Vol. 281, Issue 13, 8788-8795, March 31, 2006

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Poly(ADP-ribose) Polymerase-1 Signaling to Mitochondria in Necrotic Cell Death Requires RIP1/TRAF2-mediated JNK1 Activation^*

Yue Xu¹, Shuang Huang, Zheng-Gang Liu, and Jiahuai Han

From the Department of Immunology, The Scripps Research Institute, La Jolla, California 92037 and Cell and Cancer Biology Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892

Poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation-induced necrosis has been implicated in several pathophysiological conditions. Although mitochondrial dysfunction and apoptosis-inducing factor translocation from the mitochondria to the nucleus have been suggested to play very important roles in PARP-1-mediated cell death, the signaling events downstream of PARP-1 activation in initiating mitochondria dysfunction are not clear. Here we used the DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine, a potent PARP-1 activator, to study PARP-1 activation-mediated cell death. We found, based on genetic knockouts and pharmacological inhibition, that c-Jun N-terminal kinase (JNK), especially JNK1, but not the other groups of mitogen-activated protein kinase, is required for PARP-1-induced mitochondrial dysfunction, apoptosis-inducing factor translocation, and subsequent cell death. We reveal that receptor-interacting protein 1 (RIP1) and tumor necrosis factor receptor-associated factor 2 (TRAF2), are upstream of JNK in PARP-1 hyperactivated cells, because PARP-1-induced JNK activation was attenuated in RIP1-/- and TRAF2-/- mouse embryonic fibroblast cells. Consistently, knockouts of RIP1 and TRAF2 caused a resistance to PARP-1-induced cell death. Therefore, our study uncovers that RIP1, TRAF2, and JNK comprise a pathway to mediate the signaling from PARP-1 overactivation to mitochondrial dysfunction.

Received for publication, July 25, 2005 , and in revised form, December 30, 2005.

^* This work was supported in part by National Institutes of Health Grants AI41637, AI054796, GM67101, and GM37696. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Immunology, The Scripps Research Inst., 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-8719; Fax: 858-784-8665; E-mail: mcbxuyue{at}scripps.edu.

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