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J. Biol. Chem., Vol. 279, Issue 7, 5405-5412, February 13, 2004
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From the
Departments of Pathology and Interdisciplinary Oncology, University of South Florida College of Medicine and H. Lee Moffitt Cancer Center, Tampa, Florida 33612, the Cancer Research Department, Berlex Biosciences, Richmond, California 94804, and the ¶Department of Obstetrics & Gynaecology and Cellular & Molecular Medicine, University of Ottawa, Ottawa Health Research Institute, The Ottawa Hospital (Civic Campus), Ottawa K1Y 4E9, Canada
Akt negatively regulates apoptotic pathways at a premitochondrial level through phosphorylation and modulation of proteins such as Bad, Forkhead proteins, and GSK-3
. Akt has also been shown to protect cell death at a post-mitochondrial level, although its downstream targets have not been well documented. Here, we demonstrate that Akt, including AKT1 and AKT2, interacts with and phosphorylates X-linked inhibitor of apoptosis protein (XIAP) at residue serine-87 in vitro and in vivo. Phosphorylation of XIAP by Akt protects XIAP from ubiquitination and degradation in response to cisplatin. Moreover, autoubiquitination of XIAP is also inhibited by Akt. Consistent with this, an XIAP mutant introduced into cells which mimics the Akt-phosphorylated form (i.e. XIAP-S87D) displays reduced ubiquitination and degradation as compared with wild type XIAP. The greater stability of XIAP-S87D in cells translated to increased cell survival after cisplatin treatment. Conversely, a mutant that could not be phosphorylated by Akt (XIAP-S87A) was more rapidly degraded and showed increased cisplatin-induced apoptosis. Furthermore, suppression of XIAP by either siRNA or adenovirus of antisense of XIAP induced programmed cell death and inhibited Akt-stimulated cell survival in ovarian cancer cells. These data identify XIAP as a new downstream target of Akt and a potentially important mediator of the effect of Akt on cell survival.
Received for publication, November 3, 2003 , and in revised form, November 25, 2003.
* This work was supported in part by NCI National Institutes of Health Grants CA77935 and CA89242, Department of Defense Grants DAMD 17-01-1-0394 and DAMD 17-02-1-0670, Canadian Institutes of Health Research Grant MOP-15691, and National Cancer Institute of Canada Grant 013335 (with funds from the Canadian Cancer Society). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|| To whom correspondence should be addressed: Dept. of Pathology, University of South Florida College of Medicine and H. Lee Moffitt Cancer Center, 12901 Bruce B. Downs Blvd., MDC Box 11, Tampa, FL 33612. Tel.: 813-974-8595; Fax: 813-974-5536; E-mail: jcheng{at}hsc.usf.edu.
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