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J. Biol. Chem., Vol. 282, Issue 17, 13059-13072, April 27, 2007

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XAF1 Mediates Tumor Necrosis Factor--induced Apoptosis and X-linked Inhibitor of Apoptosis Cleavage by Acting through the Mitochondrial Pathway^*

Shawn L. Straszewski-Chavez, Irene P. Visintin, Natasha Karassina^¶, Georgyi Los^¶, Peter Liston^||, Ruth Halaban^**, Ahmed Fadiel, and Gil Mor¹

From the Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06520, the Departments of Obstetrics, Gynecology, and Reproductive Sciences and ^**Dermatology, Yale University School of Medicine, New Haven, Connecticut 06520, ^¶Promega Corporation, Madison, Wisconsin 53711, and the ^||Department of Pediatrics, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada

Tumor necrosis factor- (TNF-) and Fas ligand induce apoptosis by interacting with their corresponding membrane-bound death receptors and activating caspases. Since both systems share several components of the intracellular apoptotic cascade and are expressed by first trimester trophoblasts, it is unknown how these cells remain resistant to Fas ligand while sensitive to TNF-. XAF1 (X-linked inhibitor of apoptosis (XIAP)-associated factor 1) is a proapoptotic protein that antagonizes the caspase-inhibitory activity of XIAP. Here, we demonstrated that XAF1 functions as an alternative pathway for TNF--induced apoptosis by translocating to the mitochondria and promoting XIAP inactivation. In addition, we showed that the overexpression of XAF1 sensitized first trimester trophoblast cells to Fas-mediated apoptosis. Furthermore, we also determined that the differential expression of XAF1 in first and third trimester trophoblast cells was due to changes in XAF1 gene methylation. Our results establish a novel regulatory pathway controlling trophoblast cell survival and provide a molecular mechanism to explain trophoblast sensitivity to TNF- and the increased number of apoptotic trophoblast cells observed near term. Aberrant XAF1 expression and/or localization may have consequences for normal pregnancy outcome.

Received for publication, September 22, 2006 , and in revised form, January 24, 2007.

^* 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.

¹ To whom correspondence should be addressed: Dept. of Obstetrics, Gynecology, and Reproductive Sciences, Reproductive Immunology Unit, Yale University School of Medicine, 333 Cedar St., FMB 301, New Haven, CT 06520. Tel.: 203-785-6294; Fax: 203-785-4883; E-mail: Gil.Mor{at}yale.edu.

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