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Molecular and Cellular Biology, August 2004, p. 7003-7014, Vol. 24, No. 16
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.16.7003-7014.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Upstream Regulatory Role for XIAP in Receptor-Mediated Apoptosis{dagger}

John C. Wilkinson,1 Enrique Cepero,2 Lawrence H. Boise,2 and Colin S. Duckett1,3*

Departments of Pathology,1 Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109,3 Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida 331012

Received 19 December 2003/ Returned for modification 27 February 2004/ Accepted 26 April 2004

X-linked inhibitor of apoptosis (XIAP) is an endogenous inhibitor of cell death that functions by suppressing caspases 3, 7, and 9. Here we describe the establishment of Jurkat-derived cell lines stably overexpressing either full-length XIAP or a truncation mutant of XIAP that can only inhibit caspase 9. Characterization of these cell lines revealed that following CD95 activation full-length XIAP supported both short- and long-term survival as well as proliferative capacity, in contrast to the truncation mutant but similar to Bcl-xL. Full-length XIAP was also able to inhibit CD95-mediated caspase 3 processing and activation, the mitochondrial release of cytochrome c and Smac/DIABLO, and the loss of mitochondrial membrane potential, whereas the XIAP truncation mutant failed to prevent any of these cell death events. Finally, suppression of XIAP levels by RNA interference sensitized Bcl-xL-overexpressing cells to death receptor-induced apoptosis. These data demonstrate for the first time that full-length XIAP inhibits caspase activation required for mitochondrial amplification of death receptor signals and that, by acting upstream of mitochondrial activation, XIAP supports the long-term proliferative capacity of cells following CD95 stimulation.

* Corresponding author. Mailing address: Med Sci I, Room 5315, 1301 Catherine, Ann Arbor, MI 48109-0602. Phone: (734) 615-6414. Fax: (734) 615-7012. E-mail: colind{at}umich.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2004, p. 7003-7014, Vol. 24, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.16.7003-7014.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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