Poly(ADP-ribose) polymerase-1 signaling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK1 activation

Yue Xu, Shuang Huang, Zheng Gang Liu, Jiahuai Han

Research output: Contribution to journalArticle

190 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8788-8795
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number13
DOIs
StatePublished - Mar 31 2006

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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Receptor-Interacting Protein Serine-Threonine Kinases
Death Domain Receptors
Mitochondria
Poly(ADP-ribose) Polymerases
Cell death
Cell Death
Chemical activation
Apoptosis Inducing Factor
Phosphotransferases
Poly (ADP-Ribose) Polymerase-1
Methylnitronitrosoguanidine
JNK Mitogen-Activated Protein Kinases
Alkylating Agents
Fibroblasts
Mitogen-Activated Protein Kinases
Necrosis

ASJC Scopus subject areas

  • Biochemistry

Cite this

Poly(ADP-ribose) polymerase-1 signaling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK1 activation. / Xu, Yue; Huang, Shuang; Liu, Zheng Gang; Han, Jiahuai.

In: Journal of Biological Chemistry, Vol. 281, No. 13, 31.03.2006, p. 8788-8795.

Research output: Contribution to journalArticle

Xu, Yue ; Huang, Shuang ; Liu, Zheng Gang ; Han, Jiahuai. / Poly(ADP-ribose) polymerase-1 signaling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK1 activation. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 13. pp. 8788-8795.
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