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J Biol Chem. 2002 Nov 8;277(45):43224-32. Epub 2002 Aug 28.

c-Myc augments the apoptotic activity of cytosolic death receptor signaling proteins by engaging the mitochondrial apoptotic pathway.

Author information

1
University of California, San Francisco Comprehensive Cancer Center, San Francisco, Calfornia 94115, USA.

Abstract

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.

PMID:
12202489
DOI:
10.1074/jbc.M206967200
[Indexed for MEDLINE]
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