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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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Q.-H. Yang and C. Du (2004)
J. Biol. Chem. 279, 16963-16970
   Abstract »    Full Text »    PDF »
Suppression of caspase-8- and -10-associated RING proteins results in sensitization to death ligands and inhibition of tumor cell growth.
E. R. McDonald III and W. S. El-Deiry (2004)
PNAS 101, 6170-6175
   Abstract »    Full Text »    PDF »
Motoneuron Resistance to Apoptotic Cell Death In Vivo Correlates with the Ratio between X-Linked Inhibitor of Apoptosis Proteins (XIAPs) and Its Inhibitor, XIAP-Associated Factor 1.
D. Perrelet, F. E. Perrin, P. Liston, R. G. Korneluk, A. MacKenzie, M. Ferrer-Alcon, and A. C. Kato (2004)
J. Neurosci. 24, 3777-3785
   Abstract »    Full Text »    PDF »
PR39 Inhibits Apoptosis in Hypoxic Endothelial Cells: Role of Inhibitor Apoptosis Protein-2.
J. Wu, C. Parungo, G. Wu, P. M. Kang, R. J. Laham, F. W. Sellke, M. Simons, and J. Li (2004)
Circulation 109, 1660-1667
   Abstract »    Full Text »    PDF »
DUB-3, a Cytokine-inducible Deubiquitinating Enzyme That Blocks Proliferation.
J. F. Burrows, M. J. McGrattan, A. Rascle, M. Humbert, K.-H. Baek, and J. A. Johnston (2004)
J. Biol. Chem. 279, 13993-14000
   Abstract »    Full Text »    PDF »
Cotreatment with Histone Deacetylase Inhibitor LAQ824 Enhances Apo-2L/Tumor Necrosis Factor-Related Apoptosis Inducing Ligand-Induced Death Inducing Signaling Complex Activity and Apoptosis of Human Acute Leukemia Cells.
F. Guo, C. Sigua, J. Tao, P. Bali, P. George, Y. Li, S. Wittmann, L. Moscinski, P. Atadja, and K. Bhalla (2004)
Cancer Res. 64, 2580-2589
   Abstract »    Full Text »    PDF »
Uncoupling of the Signaling and Caspase-inhibitory Properties of X-linked Inhibitor of Apoptosis.
J. Lewis, E. Burstein, S. B. Reffey, S. B. Bratton, A. B. Roberts, and C. S. Duckett (2004)
J. Biol. Chem. 279, 9023-9029
   Abstract »    Full Text »    PDF »
Translation of cellular inhibitor of apoptosis protein 1 (c-IAP1) mRNA is IRES mediated and regulated during cell stress.
M. E. VAN EDEN, M. P. BYRD, K. W. SHERRILL, and R. E. LLOYD (2004)
RNA 10, 469-481
   Abstract »    Full Text »    PDF »
Akt Phosphorylation and Stabilization of X-linked Inhibitor of Apoptosis Protein (XIAP).
H. C. Dan, M. Sun, S. Kaneko, R. I. Feldman, S. V. Nicosia, H.-G. Wang, B. K. Tsang, and J. Q. Cheng (2004)
J. Biol. Chem. 279, 5405-5412
   Abstract »    Full Text »    PDF »
Unlike Diablo/smac, Grim Promotes Global Ubiquitination and Specific Degradation of X Chromosome-linked Inhibitor of Apoptosis (XIAP) and Neither Cause Apoptosis.
J. Silke, T. Kratina, P. G. Ekert, M. Pakusch, and D. L. Vaux (2004)
J. Biol. Chem. 279, 4313-4321
   Abstract »    Full Text »    PDF »
Tumor Necrosis Factor Receptor-associated Factor (TRAF) 1 Regulates CD40-induced TRAF2-mediated NF-{kappa}B Activation.
M. Fotin-Mleczek, F. Henkler, A. Hausser, H. Glauner, D. Samel, A. Graness, P. Scheurich, D. Mauri, and H. Wajant (2004)
J. Biol. Chem. 279, 677-685
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Role of Ubiquitin Carboxy Terminal Hydrolase-L1 in Neural Cell Apoptosis Induced by Ischemic Retinal Injury in Vivo.
T. Harada, C. Harada, Y.-L. Wang, H. Osaka, K. Amanai, K. Tanaka, S. Takizawa, R. Setsuie, M. Sakurai, Y. Sato, et al. (2004)
Am. J. Pathol. 164, 59-64
   Abstract »    Full Text »    PDF »
The ubiquitin-proteasome system in cardiovascular diseases--a hypothesis extended.
J. Herrmann, A. Ciechanover, L. O Lerman, and A. Lerman (2004)
Cardiovasc Res 61, 11-21
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Autoubiquitylation of the V(D)J recombinase protein RAG1.
J. M. Jones and M. Gellert (2003)
PNAS 100, 15446-15451
   Abstract »    Full Text »    PDF »
Harnessing Apoptosis for Improved Anticancer Gene Therapy.
D. J. Waxman and P. S. Schwartz (2003)
Cancer Res. 63, 8563-8572
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Regulation of survivin function by Hsp90.
P. Fortugno, E. Beltrami, J. Plescia, J. Fontana, D. Pradhan, P. C. Marchisio, W. C. Sessa, and D. C. Altieri (2003)
PNAS 100, 13791-13796
   Abstract »    Full Text »    PDF »


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