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Molecular and Cellular Biology, November 2006, p. 8136-8148, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.00257-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Distinct Signaling Pathways in TRAIL- versus Tumor Necrosis Factor-Induced Apoptosis{triangledown} ,{ddagger}

Zhaoyu Jin{dagger} and Wafik S. El-Deiry*

Laboratory of Molecular Oncology and Cell Cycle Regulation, Departments of Medicine (Hematology/Oncology), Genetics, and Pharmacology, Institute for Translational Medicine and Therapeutics and Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Received 10 February 2006/ Returned for modification 19 May 2006/ Accepted 8 August 2006

Trimeric tumor necrosis factor (TNF) binding leads to recruitment of TRADD to TNFR1. In current models, TRADD recruits RIP, TRAF2, and FADD to activate NF-{kappa}B, Jun N-terminal protein kinase (JNK), and apoptosis. Using stable short-hairpin RNA (shRNA) knockdown (KD) cells targeting these adaptors, TNF death-inducing signaling complex immunoprecipitation demonstrates competitive binding of TRADD and RIP to TNFR1, whereas TRAF2 recruitment requires TRADD. Analysis of KD cells indicates that FADD is necessary for Fas-L- or TRAIL- but not TNF-induced apoptosis. Interestingly, TRADD is dispensable, while RIP is required for TNF-induced apoptosis in human tumor cells. TRADD is required for c-Jun phosphorylation upon TNF exposure. RIP KD abrogates formation of complex II following TNF exposure, whereas TRADD KD allows efficient RIP-caspase 8 association. Treatment with TRAIL also induces formation of a complex II containing FADD, RIP, IKK{alpha}, and caspase 8 and 10, leading to activation of caspase 8. Our data suggest that TNF triggers apoptosis in a manner distinct from that of Fas-L or TRAIL.

* Corresponding author. Mailing address: University of Pennsylvania School of Medicine, 415 Curie Blvd., CRB 437A, Philadelphia, PA 19104. Phone: (215) 898-9015. Fax: (215) 573-9139. E-mail: wafik{at}mail.med.upenn.edu.

{triangledown} Published ahead of print on 28 August 2006.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} Current address: Molecular Oncology, Genentech, Inc., South San Francisco, CA 94080.

Molecular and Cellular Biology, November 2006, p. 8136-8148, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.00257-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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