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EMBO J. 2007 Feb 21;26(4):1055-67. Epub 2007 Feb 1.

c-Myc primed mitochondria determine cellular sensitivity to TRAIL-induced apoptosis.

Author information

1
Cancer Cell Circuitry Laboratory, Institute of Biomedicine/Biochemistry and Molecular Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.

Abstract

Oncogenic c-Myc renders cells sensitive to TRAIL-induced apoptosis, and existing data suggest that c-Myc sensitizes cells to apoptosis by promoting activation of the mitochondrial apoptosis pathway. However, the molecular mechanisms linking the mitochondrial effects of c-Myc to the c-Myc-dependent sensitization to TRAIL have remained unresolved. Here, we show that TRAIL induces a weak activation of procaspase-8 but fails to activate mitochondrial proapoptotic effectors Bax and Bak, cytochrome c release or downstream effector caspase-3 in non-transformed human fibroblasts or mammary epithelial cells. Our data is consistent with the model that activation of oncogenic c-Myc primes mitochondria through a mechanism involving activation of Bak and this priming enables weak TRAIL-induced caspase-8 signals to activate Bax. This results in cytochrome c release, activation of downstream caspases and postmitochondrial death-inducing signaling complex -independent augmentation of caspase-8-Bid activity. In conclusion, c-Myc-dependent priming of the mitochondrial pathway is critical for the capacity of TRAIL-induced caspase-8 signals to activate effector caspases and for the establishment of lethal caspase feedback amplification loop in human cells.

PMID:
17268552
PMCID:
PMC1852827
DOI:
10.1038/sj.emboj.7601551
[Indexed for MEDLINE]
Free PMC Article

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