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.
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Abbreviations
- ROS:
-
reactive oxygen species
- H2O2:
-
hydrogen peroxide
- JNK:
-
c-Jun N-terminal kinase
- PARP-1:
-
poly (ADP-ribose) polymerase-1
- PAR:
-
poly (ADP-ribose)
- NAD+:
-
β-nicotinamide adenine dinucleotide
- AIF:
-
apoptosis-inducing factor
- RIP:
-
receptor-interacting protein
- TRAF2:
-
tumor necrosis factor receptor (TNFR)-associated factor 2
- 3AB:
-
3amino benzamide
- AO:
-
acridine orange
- EB:
-
ethidium bromide
- MNNG:
-
N-methyl-N′-nitro-N-nitrosoguanidine
References
Sies H . Oxidative stress: oxidants and antioxidants. Exp Physiol 1997; 82: 291–295.
Rhee SG . Cell signaling H2O2 a necessary evil for cell signaling. Science 2006; 312: 1882–1883.
Kwon YW, Masutani H, Nakamura H, Ishii Y, Yodoi J . Redox regulation of cell growth and cell death. Biol Chem 2003; 384: 991–996.
Hampton MB, Orrenius S . Redox regulation of apoptotic cell death. Biofactors 1998; 8: 1–5.
Tang DG, La E, Kern J, Kehrer JP . Fatty acid oxidation and signaling in apoptosis. Biol Chem 2002; 383: 425–442.
Gardner AM, Xu FH, Fady C, Jacoby FJ, Duffey DC, Tu Y et al. Apoptotic vs. nonapoptotic cytotoxicity induced by hydrogen peroxide. Free Radic Biol Med 1997; 22: 73–83.
Shen HM, Pervaiz S . TNF receptor superfamily-induced cell death: redox-dependent execution. FASEB J 2006; 20: 1589–1598.
Garg AK, Aggarwal BB . Reactive oxygen intermediates in TNF signaling. Mol Immunol 2002; 39: 509–517.
Virag L . Structure and function of poly(ADP-ribose) polymerase-1: role in oxidative stress-related pathologies. Curr Vasc Pharmacol 2005; 3: 209–214.
Herceg Z, Wang ZQ . Failure of poly(ADP-ribose) polymerase cleavage by caspases leads to induction of necrosis and enhanced apoptosis. Mol Cell Biol 1999; 19: 5124–5133.
Koh DW, Dawson TM, Dawson VL . Mediation of cell death by poly(ADP-ribose) polymerase-1. Pharmacol Res 2005; 52: 5–14.
Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ et al. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 2002; 297: 259–263.
Johnson GL, Lapadat R . Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002; 298: 1911–1912.
Lei K, Nimnual A, Zong WX, Kennedy NJ, Flavell RA, Thompson CB et al. The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH(2)-terminal kinase. Mol Cell Biol 2002; 22: 4929–4942.
Deng X, Xiao L, Lang W, Gao F, Ruvolo P, May Jr WS . Novel role for JNK as a stress-activated Bcl2 kinase. J Biol Chem 2001; 276: 23681–23688.
Shen HM, Lin Y, Choksi S, Tran J, Jin T, Chang L et al. Essential roles of receptor-interacting protein and TRAF2 in oxidative stress-induced cell death. Mol Cell Biol 2004; 24: 5914–5922.
Bouchard VJ, Rouleau M, Poirier GG . PARP-1, a determinant of cell survival in response to DNA damage. Exp Hematol 2003; 31: 446–454.
Ha HC, Snyder SH . Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci USA 1999; 96: 13978–13982.
Xu Y, Huang S, Liu ZG, Han J . Poly(ADP-ribose) polymerase-1 signaling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK1 activation. J Biol Chem 2006; 281: 8788–8795.
Van Gool L, Meyer R, Tobiasch E, Cziepluch C, Jauniaux JC, Mincheva A et al. Overexpression of human poly(ADP-ribose) polymerase in transfected hamster cells leads to increased poly(ADP-ribosyl)ation and cellular sensitization to gamma irradiation. Eur J Biochem 1997; 244: 15–20.
Deng Y, Ren X, Yang L, Lin Y, Wu X A . JNK-dependent pathway is required for TNFalpha-induced apoptosis. Cell 2003; 115: 61–70.
Cavigelli M, Dolfi F, Claret FX, Karin M . Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation. Embo J 1995; 14: 5957–5964.
Lindahl T, Satoh MS, Poirier GG, Klungland A . Post-translational modification of poly(ADP-ribose) polymerase induced by DNA strand breaks. Trends Biochem Sci 1995; 20: 405–411.
Leppa S, Bohmann D . Diverse functions of JNK signaling and c-Jun in stress response and apoptosis. Oncogene 1999; 18: 6158–6162.
Kauppinen TM, Chan WY, Suh SW, Wiggins AK, Huang EJ, Swanson RA . Direct phosphorylation and regulation of poly(ADP-ribose) polymerase-1 by extracellular signal-regulated kinases 1/2. Proc Natl Acad Sci USA 2006; 103: 7136–7141.
Nakano H, Nakajima A, Sakon-Komazawa S, Piao JH, Xue X, Okumura K . Reactive oxygen species mediate crosstalk between NF-kappaB and JNK. Cell Death Differ 2006; 13: 730–737.
Tobiume K, Matsuzawa A, Takahashi T, Nishitoh H, Morita K, Takeda K et al. ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep 2001; 2: 222–228.
Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M . Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 2005; 120: 649–661.
Lin Y, Choksi S, Shen HM, Yang QF, Hur GM, Kim YS et al. Tumor necrosis factor-induced nonapoptotic cell death requires receptor-interacting protein-mediated cellular reactive oxygen species accumulation. J Biol Chem 2004; 279: 10822–10828.
Kim MY, Zhang T, Kraus WL . Poly(ADP-ribosyl)ation by PARP-1: ‘PAR-laying’ NAD+ into a nuclear signal. Genes Dev 2005; 19: 1951–1967.
Chiarugi A . Poly(ADP-ribose) polymerase: killer or conspirator? The ‘suicide hypothesis’ revisited. Trends Pharmacol Sci 2002; 23: 122–129.
Zahradka P, Ebisuzaki K . A shuttle mechanism for DNA-protein interactions. The regulation of poly(ADP-ribose) polymerase. Eur J Biochem 1982; 127: 579–585.
Ariumi Y, Masutani M, Copeland TD, Mimori T, Sugimura T, Shimotohno K et al. Suppression of the poly(ADP-ribose) polymerase activity by DNA-dependent protein kinase in vitro. Oncogene 1999; 18: 4616–4625.
Bauer PI, Farkas G, Buday L, Mikala G, Meszaros G, Kun E et al. Inhibition of DNA binding by the phosphorylation of poly ADP-ribose polymerase protein catalysed by protein kinase C. Biochem Biophys Res Commun 1992; 187: 730–736.
Tanaka Y, Koide SS, Yoshihara K, Kamiya T . Poly (ADP-ribose) synthetase is phosphorylated by protein kinase C in vitro. Biochem Biophys Res Commun 1987; 148: 709–717.
Walker JW, Jijon HB, Madsen KL . AMP-activated protein kinase is a positive regulator of poly(ADP-ribose) polymerase. Biochem Biophys Res Commun 2006; 342: 336–341.
Andreone TL, O'Connor M, Denenberg A, Hake PW, Zingarelli B . Poly(ADP-ribose) polymerase-1 regulates activation of activator protein-1 in murine fibroblasts. J Immunol 2003; 170: 2113–2120.
Wang ZQ, Auer B, Stingl L, Berghammer H, Haidacher D, Schweiger M et al. Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease. Genes Dev 1995; 9: 509–520.
McGahon AJ, Martin SJ, Bissonnette RP, Mahboubi A, Shi Y, Mogil RJ et al. The end of the (cell) line: methods for the study of apoptosis in vitro. Methods Cell Biol 1995; 46: 153–185.
Acknowledgements
We thank Prof. Alexander Bürkle (German Cancer Research Center) for providing us the PARP-1 expression vector. We also thank Drs. GM Hur, S Choksi, Mr. YB Ong and Ms M Zhao for their technical support. This study was in part supported by a NCI oncology fellowship (to HM Shen) and research grants from the National University of Singapore (startup grant and provost matching grant to HM Shen).
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Zhang, S., Lin, Y., Kim, YS. et al. c-Jun N-terminal kinase mediates hydrogen peroxide-induced cell death via sustained poly(ADP-ribose) polymerase-1 activation. Cell Death Differ 14, 1001–1010 (2007). https://doi.org/10.1038/sj.cdd.4402088
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DOI: https://doi.org/10.1038/sj.cdd.4402088
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