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Molecular and Cellular Biology, July 2004, p. 5914-5922, Vol. 24, No. 13
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.13.5914-5922.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Essential Roles of Receptor-Interacting Protein and TRAF2 in Oxidative Stress-Induced Cell Death

Han-Ming Shen,1,2 Yong Lin,1 Swati Choksi,1 Jamie Tran,1 Tian Jin,3 Lufen Chang,4 Michael Karin,4 Jianke Zhang,5 and Zheng-gang Liu1*

Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute,1 Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland,3 Department of Community, Occupational and Family Medicine, Faculty of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore,2 Department of Pharmacology, University of California, San Diego, San Diego, California,4 Department of Microbiology & Immunology, Thomas Jefferson University Medical College, Philadelphia, Pennsylvania5

Received 4 September 2003/ Returned for modification 27 October 2003/ Accepted 29 March 2004

Oxidative stress and reactive oxygen species (ROS) can elicit and modulate various physiological and pathological processes, including cell death. However, the mechanisms controlling ROS-induced cell death are largely unknown. Data from this study suggest that receptor-interacting protein (RIP) and tumor necrosis factor receptor (TNFR)-associated factor 2 (TRAF2), two key effector molecules of TNF signaling, are essential for ROS-induced cell death. We found that RIP–/– or TRAF2–/– mouse embryonic fibroblasts (MEF) are resistant to ROS-induced cell death when compared to wild-type cells, and reconstitution of RIP and TRAF2 gene expression in their respective deficient MEF cells restored their sensitivity to H2O2-induced cell death. We also found that RIP and TRAF2 form a complex upon H2O2 exposure, but without the participation of TNFR1. The colocalization of RIP with a membrane lipid raft marker revealed a possible role of lipid rafts in the transduction of cell death signal initiated by H2O2. Finally, our results demonstrate that activation of c-Jun NH2-terminal kinase 1 is a critical event downstream of RIP and TRAF2 in mediating ROS-induced cell death. Therefore, our study uncovers a novel signaling pathway regulating oxidative stress-induced cell death.

* Corresponding author. Mailing address: Cell and Cancer Biology Branch, NCI, NIH, Bldg. 10, Rm. 6N105, 9000 Rockville Pike, Bethesda, MD 20892. Phone: (301) 435-6351. Fax: (301) 402-1997. E-mail: zgliu{at}helix.nih.gov.

Molecular and Cellular Biology, July 2004, p. 5914-5922, Vol. 24, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.13.5914-5922.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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