c-Myc-induced sensitization to apoptosis is mediated through cytochrome c release

  1. Philippe Juin,
  2. Anne-Odile Hueber,
  3. Trevor Littlewood, and
  4. Gerard Evan
  1. Imperial Cancer Research Fund, London WC2A 3PX, UK

Abstract

Expression of c-Myc sensitizes cells to a wide range of pro-apoptotic stimuli. We here show that this pro-apoptotic effect is mediated through release of mitochondrial holocytochrome c into the cytosol. First, activation of c-Myc triggers release of cytochromec from mitochondria. This release is caspase-independent and blocked by the survival factor IGF-1. Second, c-Myc-induced apoptosis is blocked by microinjection of anticytochrome c antibody. In addition, we show that microinjection of holocytochrome cmimics the effect of c-Myc activation, sensitizing cells to DNA damage and to the CD95 pathway. Both p53 and CD95/Fas signaling have been implicated in c-Myc-induced apoptosis but neither was required for c-Myc-induced cytochrome c release. Nonetheless, inhibition of CD95 signaling in fibroblasts did prevent c-Myc-induced apoptosis, apparently by obstructing the ability of cytosolic cytochrome c to activate caspases. We conclude that c-Myc promotes apoptosis by causing the release of cytochrome c, but the ability of cytochrome c to activate apoptosis is critically dependent upon other signals.

Keywords

Footnotes

  • Corresponding author.

  • E-MAIL G.Evan{at}icrf.icnet.uk; FAX 44 171 269 3581.

    • Received March 24, 1999.
    • Accepted April 20, 1999.
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