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

James W Peacock1, Jodie Palmer, Dieter Fink

  • 1The Prostate Centre at Vancouver General Hospital, University of British Columbia, 2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6.

Molecular and Cellular Biology
|December 24, 2008
PubMed

Insights

The PTEN tumor suppressor determines cell death pathways after CD95/Fas receptor stimulation. PTEN loss or gain converts apoptosis signaling between mitochondrially dependent and independent routes.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The CD95/Fas receptor triggers two distinct apoptosis pathways: Type I (mitochondria-independent) and Type II (mitochondria-dependent).
  • The molecular mechanisms differentiating these pathways remain largely unknown.

Purpose of the Study:

  • To investigate the role of the PTEN tumor suppressor in regulating Fas-mediated apoptosis pathways.
  • To determine if PTEN influences the switch between Type I and Type II Fas signaling.

Main Methods:

  • Analysis of 24 Fas-sensitive tumor lines to correlate PTEN expression/activity with Fas signaling.
  • Loss-of-function and gain-of-function studies of PTEN.
  • Analysis of Bcl-2 transgenic Pten(+/-) mice, focusing on primary thymocytes and activated T lymphocytes.
  • Investigation of PTEN's influence on PEA-15 phosphorylation and activity.

Main Results:

  • PTEN expression/activity strongly correlates with the distinct Type I and Type II Fas apoptosis pathways.
  • PTEN manipulation (loss/gain) can interconvert cells between Type I and Type II Fas pathways.
  • Pten haploinsufficiency converts Fas-induced apoptosis into a Bcl-2-sensitive response in lymphocytes.
  • PTEN regulates PEA-15 phosphorylation, impacting Bcl-2's ability to suppress Fas-induced apoptosis.

Conclusions:

  • PTEN acts as a critical molecular rheostat controlling the choice between Type I and Type II Fas apoptosis.
  • PTEN's regulation of PEA-15 is a key mechanism through which it influences Fas signaling and apoptosis outcome.

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