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Molecular and Cellular Biology, March 2009, p. 1222-1234, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.01660-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

PTEN Loss Promotes Mitochondrially Dependent Type II Fas-Induced Apoptosis via PEA-15{triangledown}

James W. Peacock,1,2 Jodie Palmer,1,2 Dieter Fink,1,2 Stephen Ip,1,2 Eric M. Pietras,5 Alice L.-F. Mui,2 Stephen W. Chung,2 Martin E. Gleave,1,3 Michael E. Cox,1,3 Ramon Parsons,4 Marcus E. Peter,5 and Christopher J. Ong1,2*

The Prostate Centre at Vancouver General Hospital,1 Departments of Surgery,2 Urological Sciences, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada,3 Department of Pathology and Medicine, Institute for Cancer Genetics, Columbia University, 1150 St. Nicholas Avenue, RBP 302, New York, New York,4 Ben May Department for Cancer, University of Chicago, Chicago, Illinois 606375

Received 24 October 2008/ Returned for modification 7 December 2008/ Accepted 10 December 2008

Two distinct biochemical signals are delivered by the CD95/Fas death receptor. The molecular basis for the differential mitochondrially independent (type I) and mitochondrially dependent (type II) Fas apoptosis pathways is unknown. By analyzing 24 Fas-sensitive tumor lines, we now demonstrate that expression/activity of the PTEN tumor suppressor strongly correlates with the distinct Fas signals. PTEN loss-of-function and gain-of-function studies demonstrate the ability to interconvert between type I and type II Fas pathways. Importantly, from analyses of Bcl-2 transgenic Pten+/– mice, Pten haploinsufficiency converts Fas-induced apoptosis from a Bcl-2-independent to a Bcl-2-sensitive response in primary thymocytes and activated T lymphocytes. We further show that PTEN influences Fas signaling, at least in part, by regulating PEA-15 phosphorylation and activity that, in turn, regulate the ability of Bcl-2 to suppress Fas-induced apoptosis. Thus, PTEN is a key molecular rheostat that determines whether a cell dies by a mitochondrially independent type I versus a mitochondrially dependent type II apoptotic pathway upon Fas stimulation.

* Corresponding author. Mailing address: The Prostate Centre at Vancouver General Hospital, University of British Columbia, 2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6. Phone: (604) 875-5555, ext. 63120. Fax: (604) 875-5654. E-mail: chriso{at}interchange.ubc.ca

{triangledown} Published ahead of print on 22 December 2008.

Molecular and Cellular Biology, March 2009, p. 1222-1234, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.01660-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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