title: PTEN loss promotes mitochondrially dependent type II Fas-induced apoptosis via PEA-15.
abstract: 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.
authors.affiliation: The Prostate Centre at Vancouver General Hospital, University of British Columbia, 2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: James W
authors.initials: JW
authors.lastname: Peacock
authors.forename: Jodie
authors.initials: J
authors.lastname: Palmer
authors.forename: Dieter
authors.initials: D
authors.lastname: Fink
authors.forename: Stephen
authors.initials: S
authors.lastname: Ip
authors.forename: Eric M
authors.initials: EM
authors.lastname: Pietras
authors.forename: Alice L-F
authors.initials: AL
authors.lastname: Mui
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Chung
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cox
authors.forename: Ramon
authors.initials: R
authors.lastname: Parsons
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Peter
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ong
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction; D019014:fas Receptor / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; C092039:PEA15 protein, human; C490444:Pea15 protein, mouse; D010750:Phosphoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse