Bar membrane insertion during Fas(CD95)-induced apoptosis precedes cytochrome c release and is inhibited by Bcl-2

Kathleen M. Murphy, Uldis N. Streips, Richard B. Lock

Research output: Contribution to journalArticlepeer-review

Abstract

Ligation of the Fas cell surface receptor leads to activation of caspases and subsequent apoptosis. Members of the Bcl-2 family of proteins control the cellular commitment to apoptosis, although their role in Fas-induced apoptosis is ill-defined. In this report we Demonstrate that the pro-apoptotic protein, Bax, translocates from the cytosol specifically to the mitochondria following Fas ligation in MCF10A1 breast epithelial cells. Bax translocation was dependent on caspase activation, and preceded the release of cytochrome c and loss of mitochondrial respiratory activity. Bax translocation occurred in concert with activation of downstream caspases as determined by cleavage of a synthetic substrate, proteolysis of poly(ADP-ribose) polymerase, and processing of procaspase-3 and -7. Overexpression of the anti-apoptotic protein, Bcl-2, prevented Bax insertion, cytochrome c release, complete processing of caspase-3 and -7 and full activation of DEVD-specific cleavage activity. These data establish a role for Bax mitochondrial insertion during Fas-mediated apoptosis, and support a model in which Bax insertion amplifies the Fas apoptotic cascade through cytochrome c release and complete processing of caspases-3 and -7. In addition, our findings indicate that prevention of Bax insertion into the mitochondria represents a novel mechanism by which Bcl-2 inhibits Fas-induced apoptosis.

Original languageEnglish (US)
Pages (from-to)5991-5999
Number of pages9
JournalOncogene
Volume18
Issue number44
DOIs
StatePublished - Oct 28 1999
Externally publishedYes

Keywords

  • Bax
  • Bcl-2
  • Caspase
  • Cytochrome c
  • Fas

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Fingerprint

Dive into the research topics of 'Bar membrane insertion during Fas(CD95)-induced apoptosis precedes cytochrome c release and is inhibited by Bcl-2'. Together they form a unique fingerprint.

Cite this