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J. Biol. Chem., Vol. 277, Issue 50, 48913-48922, December 13, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/50/48913    most recent M209613200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xu, X. Articles by Cui, M.-Z. Search for Related Content PubMed PubMed Citation Articles by Xu, X. Articles by Cui, M.-Z. Social Bookmarking                      What's this?

The Novel Presenilin-1-associated Protein Is a Proapoptotic Mitochondrial Protein^*

Xuemin Xu^§, Yong-chang Shi, Wei Gao, Guozhang Mao, Guojun Zhao, Sudesh Agrawal^¶, Guy M. Chisolm^¶, Dexin Sui, and Mei-Zhen Cui

From the  Department of Pathology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996, the ^¶ Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, and the  Department of Biochemistry, Michigan State University, East Lansing, Michigan 48824

Recent studies have suggested a possible role for presenilin proteins in apoptotic cell death observed in Alzheimer's disease. The mechanism by which presenilin proteins regulate apoptotic cell death is not well understood. Using the yeast two-hybrid system, we previously isolated a novel protein, presenilin-associated protein (PSAP) that specifically interacts with the C terminus of presenilin 1 (PS1), but not presenilin 2 (PS2). Here we report that PSAP is a mitochondrial resident protein sharing homology with mitochondrial carrier protein. PSAP was detected in a mitochondria-enriched fraction, and PSAP immunofluorescence was present in a punctate pattern that colocalized with a mitochondrial marker. More interestingly, overexpression of PSAP caused apoptotic death. PSAP-induced apoptosis was documented using multiple independent approaches, including membrane blebbing, chromosome condensation and fragmentation, DNA laddering, cleavage of the death substrate poly(ADP-ribose) polymerase, and flow cytometry. PSAP-induced cell death was accompanied by cytochrome c release from mitochondria and caspase-3 activation. Moreover, the general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, which blocked cell death, did not block the release of cytochrome c from mitochondria caused by overexpression of PSAP, indicating that PSAP-induced cytochrome c release was independent of caspase activity. The mitochondrial localization and proapoptotic activity of PSAP suggest that it is an important regulator of apoptosis.

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