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J. Biol. Chem., Vol. 277, Issue 45, 43224-43232, November 8, 2002
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From the University of California, San Francisco Comprehensive
Cancer Center, San Francisco, Calfornia 94115
Activation of c-Myc sensitizes cells to apoptosis
induction by ligand-activated death receptors. Such sensitization to
death receptors by oncogenes may well be the mechanism underlying tumor cell sensitivity to tumor necrosis factor (TNF) or TNF-related apoptosis-inducing ligand (TRAIL). The mechanism by which this c-Myc-induced sensitization occurs is unclear but could involve modulation of expression of death receptors or their ligands or potentiation of the sensitivity of mitochondria to release
pro-apoptotic effectors such as holocytochrome c. Here,
we show that ectopic expression of the death receptor signaling protein
RIP (receptor-interactive protein) triggers apoptosis via a
FAS-associated death domain protein (FADD) and caspase
8-dependent pathway. Induction of apoptosis by this
intracellular activation of the death receptor signaling pathway is
significantly augmented by c-Myc expression. Moreover, c-Myc
expression strongly promotes the potential of RIP to induce cytochrome
c release from mitochondria. This implicates the
mitochondrial apoptotic pathway in this synergy, a notion confirmed
by the inability of c-Myc to sensitize to RIP killing in cells lacking
the obligate mitochondrial apoptotic effectors Bax and Bak. We conclude
that the lethality of the RIP-activated cytosolic caspase 8 pathway is
augmented by c-Myc priming mitochondria to release cytochrome c. This places the intersection of apoptotic synergy
between c-Myc and death receptor signaling downstream of the death receptors.
c-Myc Augments the Apoptotic Activity of Cytosolic Death Receptor
Signaling Proteins by Engaging the Mitochondrial Apoptotic Pathway*
,
*
This work was supported by generous donations from Barbara
and Gerson Bakar, the University of California, San Franscisco Cancer
Center, and The Finnish Academy.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of European Molecular Biology organization long-term fellowship.
§
To whom correspondence should be addressed: University of
California, San Francisco Comprehensive Cancer Center, 2340 Sutter St.,
San Francisco, CA 94115. Tel.: 415-514-0438; Fax.: 415-514-0878; E-mail: Gevan@cc.ucsf.edu.
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