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Vol. 13, No. 11, pp. 1367-1381, June 1, 1999
Imperial Cancer Research Fund, London WC2A 3PX, UK
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 cytochrome
c 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 c
mimics 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.
[Key Words: c-Myc; cytochrome c; apoptosis]
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