This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zheng, L. Articles by Lenardo, M. Search for Related Content PubMed PubMed Citation Articles by Zheng, L. Articles by Lenardo, M.

 Previous Article  |  Next Article 

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

Lixin Zheng,^1* Nicolas Bidere,¹ David Staudt,¹ Alan Cubre,¹ Jan Orenstein,² Francis K. Chan,³ and Michael Lenardo¹

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.

---

* Corresponding author. Mailing address: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, 9000 Rockville Pike, 10/11D09, Bethesda, MD 20892. Phone: (301) 496-2327. Fax: (301) 480-7352. E-mail: lzheng{at}niaid.nih.gov.

---

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

This article has been cited by other articles:

• Chen, N.-J., Chio, I. I. C., Lin, W.-J., Duncan, G., Chau, H., Katz, D., Huang, H.-L., Pike, K. A., Hao, Z., Su, Y.-W., Yamamoto, K., de Pooter, R. F., Zuniga-Pflucker, J. C., Wakeham, A., Yeh, W.-C., Mak, T. W. (2008). Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors. Proc. Natl. Acad. Sci. USA 105: 12429-12434 [Abstract] [Full Text]  
• Russo, J., Balogh, G. A., Russo, I. H., and the Fox Chase Cancer Center Hospital Network P, (2008). Full-term Pregnancy Induces a Specific Genomic Signature in the Human Breast. Cancer Epidemiol. Biomarkers Prev. 17: 51-66 [Abstract] [Full Text]  
• Zhang, R., Zhang, H., Lin, Y., Li, J., Pober, J. S., Min, W. (2007). RIP1-mediated AIP1 Phosphorylation at a 14-3-3-binding Site Is Critical for Tumor Necrosis Factor-induced ASK1-JNK/p38 Activation. J. Biol. Chem. 282: 14788-14796 [Abstract] [Full Text]  
• Fearns, C., Pan, Q., Mathison, J. C., Chuang, T.-H. (2006). Triad3A Regulates Ubiquitination and Proteasomal Degradation of RIP1 following Disruption of Hsp90 Binding. J. Biol. Chem. 281: 34592-34600 [Abstract] [Full Text]