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Originally published In Press as doi:10.1074/jbc.M910231199 on August 4, 2000

J. Biol. Chem., Vol. 275, Issue 41, 31733-31738, October 13, 2000
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XIAP Regulates DNA Damage-induced Apoptosis Downstream of Caspase-9 Cleavage*

Rakesh DattaDagger , Eiji Oki, Kazuya Endo, Verena Biedermann, Jian Ren, and Donald Kufe

From the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115

The IAP (inhibitor of apoptosis) family of anti-apoptotic proteins regulates programmed cell death. Of the six known human IAP-related proteins, XIAP is the most potent inhibitor. To study the mechanistic effects of XIAP on DNA damage-induced apoptosis, we prepared U-937 cells that stably overexpress XIAP. The results demonstrate that XIAP inhibits apoptosis induced by 1-[beta -D-arabinofuranosyl]cytosine (ara-C) and other genotoxic agents. XIAP had no detectable effect on ara-C-induced release of mitochondrial cytochrome c and attenuated cleavage of procaspase-9. In addition, we show that ara-C induces the association of XIAP with the cleaved fragments of caspase-9 and thereby inhibition of caspase-9 activity. The results also demonstrate that ara-C induces cleavage of procaspase-3 by a caspase-8-dependent mechanism and that XIAP inhibits caspase-3 activity. These results demonstrate that XIAP functions downstream of procaspase-9 cleavage as an inhibitor of both proteolytically processed caspase-9 and -3 in the cellular response to genotoxic stress.

* This work was supported by United States Public Health Service Grants GM58200 (to R. D.) and CA29431 (D. K.) from the National Institutes of Health, Department of Health and Human Services.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed. Tel.: 617-632-2939; Fax: 617-632-2933; E-mail: Rakesh_Datta@dfci.harvard.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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