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Science 5 May 2000:
Vol. 288. no. 5467, pp. 874 - 877
DOI: 10.1126/science.288.5467.874
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Reports

Ubiquitin Protein Ligase Activity of IAPs and Their Degradation in Proteasomes in Response to Apoptotic Stimuli

Yili Yang, Shengyun Fang, Jane P. Jensen, Allan M. Weissman, Jonathan D. Ashwell *

To determine why proteasome inhibitors prevent thymocyte death, we examined whether proteasomes degrade anti-apoptotic molecules in cells induced to undergo apoptosis. The c-IAP1 and XIAP inhibitors of apoptosis were selectively lost in glucocorticoid- or etoposide-treated thymocytes in a proteasome-dependent manner before death. IAPs catalyzed their own ubiquitination in vitro, an activity requiring the RING domain. Overexpressed wild-type c-IAP1, but not a RING domain mutant, was spontaneously ubiquitinated and degraded, and stably expressed XIAP lacking the RING domain was relatively resistant to apoptosis-induced degradation and, correspondingly, more effective at preventing apoptosis than wild-type XIAP. Autoubiquitination and degradation of IAPs may be a key event in the apoptotic program.

Laboratory of Immune Cell Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
*   To whom correspondence should be addressed. E-mail: jda{at}box-j.nih.gov

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Cardiovasc Res 61, 11-21
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Smac3, a Novel Smac/DIABLO Splicing Variant, Attenuates the Stability and Apoptosis-inhibiting Activity of X-linked Inhibitor of Apoptosis Protein.
J. Fu, Y. Jin, and L. J. Arend (2003)
J. Biol. Chem. 278, 52660-52672
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Autoubiquitylation of the V(D)J recombinase protein RAG1.
J. M. Jones and M. Gellert (2003)
PNAS 100, 15446-15451
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Harnessing Apoptosis for Improved Anticancer Gene Therapy.
D. J. Waxman and P. S. Schwartz (2003)
Cancer Res. 63, 8563-8572
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Interferon-{gamma}-Induced Sensitization of Colon Carcinomas to ZD9331 Targets Caspases, Downstream of Fas, Independent of Mitochondrial Signaling and the Inhibitor of Apoptosis Survivin.
J. Geller, I. Petak, K. S. Szucs, K. Nagy, D. M. Tillman, and J. A. Houghton (2003)
Clin. Cancer Res. 9, 6504-6515
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Requirement of Both the Second and Third BIR Domains for the Relief of X-linked Inhibitor of Apoptosis Protein (XIAP)-mediated Caspase Inhibition by Smac.
Y. Huang, R. L. Rich, D. G. Myszka, and H. Wu (2003)
J. Biol. Chem. 278, 49517-49522
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