PTEN loss promotes mitochondrially dependent type II fas-induced apoptosis via PEA-15

James W. Peacock, Jodie Palmer, Dieter Fink, Stephen Ip, Eric M. Pietras, Alice L F Mui, Stephen W. Chung, Martin E. Gleave, Michael E. Cox, Ramon Parsons, Marcus E. Peter, Christopher J. Ong

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1222-1234
Number of pages13
JournalMolecular and cellular biology
Volume29
Issue number5
DOIs
StatePublished - Mar 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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