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Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-κB control

Chu, Zhi-Liang, McKinsey, Timothy A., Liu, Lily, Gentry, Jennifer J., Malim, Michael H., Ballard, Dean W.·1997·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.94.19.10057
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Abstract

Members of the NF-κB/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-κB 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-κB is required for TNF-mediated induction of the gene encoding human c-IAP2. When overexpressed in mammalian cells, c-IAP2 activates NF-κB and suppresses TNF cytotoxicity. Both of these c-IAP2 activities are blocked in vivo by coexpressing a dominant form of IκB that is resistant to TNF-induced degradation. In contrast to wild-type c-IAP2, a mutant lacking the C-terminal RING domain inhibits NF-κB 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-κB via an IκB targeting mechanism. Functional coupling of NF-κB and c-IAP2 during the TNF response may provide a signal amplification loop that promotes cell survival rather than death.

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  1. [21]Uren, A. G., Pakusch, M., Hawkins, C. J., Puls, K. L. & Vaux, D. L. (1996) Proc. Natl. Acad. Sci. USA 93, 4974-4978.
  2. [23]Shu, H.-B., Takeuchi, M. & Goeddel, D. V. (1996) Proc. Natl. Acad. Sci. USA 93, 13973-13978.
  3. [32]Diatchenko, L., Lau, C. Y.-F., Campbell, A. P., Chenchik, A., Moqadam, F., Huang, B., Lukyanov, S., Lukyanov, K., Gurskaya, N., Sverdlov, E. D. & Siebert, P. D. (1996) Proc. Natl. Acad. Sci. USA 93, 6025-6030.
  4. [40]Scherer, D. C., Brockman, J. A., Chen, Z., Maniatis, T. & Ballard, D. W. (1995) Proc. Natl. Acad. Sci. USA 92, 11259-11263.
  5. [44]Miura, M., Friedlander, R. M. & Yuan, J. (1995) Proc. Natl. Acad. Sci. USA 92, 8318-8322.
  6. [46]Song, H. Y., Rothe, M. & Goeddel, D. V. (1996) Proc. Natl. Acad. Sci. USA 93, 6721-6725.

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Authors
Chu, Z.-L., McKinsey, T. A., Liu, L., Gentry, J. J., Malim, M. H., & Ballard, D. W.
Affiliations
Howard Hughes Medical Institute, Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232-0295; and Howard Hughes Medical Institute, Departments of Microbiology and Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6148
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1997-09-16
Volume
94
Issue
19
Pages
10057-10062
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.94.19.10057
Cited by
732
References
2
Language
en

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