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Suppression of Tumor Necrosis Factor-Induced Cell Death by Inhibitor of Apoptosis c-IAP2 is under NF-κ B Control

Zhi-Liang Chu, Timothy A. McKinsey, Lily Liu, Jennifer J. Gentry, Michael H. Malim and Dean W. Ballard
Proceedings of the National Academy of Sciences of the United States of America
Vol. 94, No. 19 (Sep. 16, 1997), pp. 10057-10062
Stable URL: http://www.jstor.org/stable/43158
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Suppression of Tumor Necrosis Factor-Induced Cell Death by Inhibitor of Apoptosis c-IAP2 is under NF-κ B Control
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Abstract

Members of the NF-κ B/Rel and inhibitor of apoptosis (IAP) protein families have been implicated in signal transduction programs that prevent cell death elicited by the cytokine tumor necrosis factor α (TNF). Although NF-κ B appears to stimulate the expression of specific protective genes, neither the identities of these genes nor the precise role of IAP proteins in this anti-apoptotic process are known. We demonstrate here that NF-κ B is required for TNF-mediated induction of the gene encoding human c-IAP2. When overexpressed in mammalian cells, c-IAP2 activates NF-κ B and suppresses TNF cytotoxicity. Both of these c-IAP2 activities are blocked in vivo by coexpressing a dominant form of Iκ B that is resistant to TNF-induced degradation. In contrast to wild-type c-IAP2, a mutant lacking the C-terminal RING domain inhibits NF-κ B induction by TNF and enhances TNF killing. These findings suggest that c-IAP2 is critically involved in TNF signaling and exerts positive feedback control on NF-κ B via an Iκ B targeting mechanism. Functional coupling of NF-κ B and c-IAP2 during the TNF response may provide a signal amplification loop that promotes cell survival rather than death.

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