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Science 288 (5467): 874-877

Copyright © 2000 by the American Association for the Advancement of Science

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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Cleavage of the Apoptosis Inhibitor DIAP1 by the Apical Caspase DRONC in Both Normal and Apoptotic Drosophila Cells.
I. Muro, J. C. Means, and R. J. Clem (2005)
J. Biol. Chem. 280, 18683-18688
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Overexpression of hRFI (human ring finger homologous to inhibitor of apoptosis protein type) inhibits death receptor-mediated apoptosis in colorectal cancer cells.
T. Konishi, S. Sasaki, T. Watanabe, J. Kitayama, and H. Nagawa (2005)
Mol. Cancer Ther. 4, 743-750
   Abstract »    Full Text »    PDF »
The CARD-carrying caspase Dronc is essential for most, but not all, developmental cell death in Drosophila.
D. Xu, Y. Li, M. Arcaro, M. Lackey, and A. Bergmann (2005)
Development 132, 2125-2134
   Abstract »    Full Text »    PDF »
Posttranscriptional Downregulation of c-IAP2 by the Ubiquitin Protein Ligase c-IAP1 In Vivo.
D. B. Conze, L. Albert, D. A. Ferrick, D. V. Goeddel, W.-C. Yeh, T. Mak, and J. D. Ashwell (2005)
Mol. Cell. Biol. 25, 3348-3356
   Abstract »    Full Text »    PDF »
Inhibition of Phosphatidylinositol 3'-Kinase/AKT Signaling Promotes Apoptosis of Primary Effusion Lymphoma Cells.
S. Uddin, A. R. Hussain, K. A. Al-Hussein, P. S. Manogaran, A. Wickrema, M. I. Gutierrez, and K. G. Bhatia (2005)
Clin. Cancer Res. 11, 3102-3108
   Abstract »    Full Text »    PDF »
Inhibition of the anaphase-promoting complex by the Xnf7 ubiquitin ligase.
J. B. Casaletto, L. K. Nutt, Q. Wu, J. D. Moore, L. D. Etkin, P. K. Jackson, T. Hunt, and S. Kornbluth (2005)
J. Cell Biol. 169, 61-71
   Abstract »    Full Text »    PDF »
Amsacta moorei Entomopoxvirus Inhibitor of Apoptosis Suppresses Cell Death by Binding Grim and Hid.
Q. Li, P. Liston, N. Schokman, J. M. Ho, and R. W. Moyer (2005)
J. Virol. 79, 3684-3691
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Formation of Bombyx mori nucleopolyhedrovirus IE2 nuclear foci is regulated by the functional domains for oligomerization and ubiquitin ligase activity.
N. Imai, S. Matsumoto, and W. Kang (2005)
J. Gen. Virol. 86, 637-644
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XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily conserved mechanism of IAPs.
F. L. Scott, J.-B. Denault, S. J. Riedl, H. Shin, M. Renatus, and G. S. Salvesen (2005)
EMBO J. 24, 645-655
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X-Linked Inhibitor of Apoptosis Functions as Ubiquitin Ligase toward Mature Caspase-9 and Cytosolic Smac/DIABLO.
Y. Morizane, R. Honda, K. Fukami, and H. Yasuda (2005)
J. Biochem. 137, 125-132
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The Membrane-associated Inhibitor of Apoptosis Protein, BRUCE/Apollon, Antagonizes Both the Precursor and Mature Forms of Smac and Caspase-9.
X.-B. Qiu and A. L. Goldberg (2005)
J. Biol. Chem. 280, 174-182
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Differential Regulation of Rad18 through Rad6-dependent Mono- and Polyubiquitination.
S. Miyase, S. Tateishi, K. Watanabe, K. Tomita, K. Suzuki, H. Inoue, and M. Yamaizumi (2005)
J. Biol. Chem. 280, 515-524
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Insulin Regulates Cleavage of Procaspase-9 via Binding of X Chromosome-Linked Inhibitor of Apoptosis Protein in HT-29 Cells.
J.-E. Kim and S. R. Tannenbaum (2004)
Cancer Res. 64, 9070-9075
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Dissection of DIAP1 Functional Domains via a Mutant Replacement Strategy.
T. Yokokura, D. Dresnek, N. Huseinovic, S. Lisi, E. Abdelwahid, P. Bangs, and K. White (2004)
J. Biol. Chem. 279, 52603-52612
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Neutralization of Smac/Diablo by Inhibitors of Apoptosis (IAPs): A CASPASE-INDEPENDENT MECHANISM FOR APOPTOTIC INHIBITION.
J. C. Wilkinson, A. S. Wilkinson, F. L. Scott, R. A. Csomos, G. S. Salvesen, and C. S. Duckett (2004)
J. Biol. Chem. 279, 51082-51090
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