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Molecular and Cellular Biology, May 2006, p. 3505-3513, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3505-3513.2006

Competitive Control of Independent Programs of Tumor Necrosis Factor Receptor-Induced Cell Death by TRADD and RIP1

Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892,¹ Department of Pathology, George Washington University School of Medicine, Washington, D.C.,² Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655³

Received 23 August 2005/ Returned for modification 20 October 2005/ Accepted 8 February 2006

Stimulation of tumor necrosis factor receptor 1 (TNFR1) can initiate several cellular responses, including apoptosis, which relies on caspases, necrotic cell death, which depends on receptor-interacting protein kinase 1 (RIP1), and NF-B activation, which induces survival and inflammatory responses. The TNFR-associated death domain (TRADD) protein has been suggested to be a crucial signal adaptor that mediates all intracellular responses from TNFR1. However, cells with a genetic deficiency of TRADD are unavailable, precluding analysis with mature immune cell types. We circumvented this problem by silencing TRADD expression with small interfering RNA. We found that TRADD is required for TNFR1 to induce NF-B activation and caspase-8-dependent apoptosis but is dispensable for TNFR1-initiated, RIP1-dependent necrosis. Our data also show that TRADD and RIP1 compete for recruitment to the TNFR1 signaling complex and the distinct programs of cell death. Thus, TNFR1-initiated intracellular signals diverge at a very proximal level by the independent association of two death domain-containing proteins, RIP1 and TRADD. These single transducers determine cell fate by triggering NF-B activation, apoptosis, and nonapoptotic death signals through separate and competing signaling pathways.

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