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Sci. STKE, 29 July 2003
Vol. 2003, Issue 193, p. tw295
[DOI: 10.1126/stke.2003.193.tw295]


APOPTOSIS A Complex Choice Between Life or Death

Signaling through the tumor necrosis factor (TNF) receptor 1 (TNFR1) can lead to apoptosis or cell survival. Survival depends on recruitment of the TNF receptor 1-associated death domain protein (TRADD) and receptor-interacting protein 1 (RIP1) to the TNFR1 and assembly of a signaling complex that leads to activation of nuclear factor {kappa}B (NF-{kappa}B). NF-{kappa}B stimulates the production of antiapoptotic proteins such as FLIPL (a caspase-8 inhibitor). TNFR1-mediated apoptosis has been widely assumed to involve recruitment of the adaptor Fas-associated death domain protein (FADD) and caspase-8 to the TNFR1 (see Barnhart and Peter). Micheau and Tschopp compared the response to TNF in HT1080 cells (wild-type cells) to that in a variant line that expressed a nondegradable NF-{kappa}B inhibitor [I{kappa}B (inhibitor of N{kappa}B) mutant cells]. Wild-type cells remained viable after treatment with TNF, whereas I{kappa}B mutant cells underwent apoptosis. Western analysis of cell lysates and immunoprecipitates indicated that two high-molecular-weight complexes formed after exposure to TNF: an early complex containing TNF, TNFR1, RIP1, TRADD, and TNF receptor-associated factor (TRAF2)--but not FADD or caspase-8--and a late complex containing RIP1, TRADD, TRAF2, FADD, and caspase-8, but not TNF or TNFR1. FLIPL participated in the secondary complex in the apoptosis-resistant line. The first complex was associated with the cell membrane; the second was found in the cytosol. Experiments using a FADD dominant-negative mutant indicated that RIP1 association with caspase-8 depended on FADD. Thus, TNFR1-dependent apoptosis appears to involve the sequential formation of two signaling complexes; if NF-{kappa}B pathways are activated sufficiently, FLIPL associates with the second complex and thereby inhibits apoptosis.

O. Micheau, J. Tschopp, Induction of TNF receptor 1-mediated apoptosis via two sequential signaling complexes. Cell 114, 181-190 (2003). [Online Journal]

B. C. Barnhart, M. E. Peter, The TNF receptor 1: A split personality complex. Cell 114, 148-150 (2003). [Online Journal]

Citation: A Complex Choice Between Life or Death. Sci. STKE 2003, tw295 (2003).

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