Journal
CELL DEATH AND DIFFERENTIATION
Volume 20, Issue 5, Pages 755-764Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2013.6
Keywords
apoptosis; Bcl-2 family; pRb/E2F-1; caspase; Noxa
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Funding
- Ministere de la Recherche et de l'Enseignement Superieur
- INSERM Region
- ARC [SFI20101201568]
- Fondation de France (Tumor committee)
- Region Pays de Loire
- Canceropole Grand Ouest [2010-12798]
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Although Bcl-2 family members control caspase activity by regulating mitochondrial permeability, caspases can, in turn, amplify the apoptotic process upstream of mitochondria by ill-characterized mechanisms. We herein show that treatment with a potent inhibitor of Bcl-2 and Bcl-xL, ABT-737, triggers caspase-dependent induction of the BH3-only protein, Mcl-1 inhibitor, Noxa. RNA interference experiments reveal that induction of Noxa, and subsequent cell death, rely not only on the transcription factor E2F-1 but also on its regulator pRb. In response to ABT-737, pRb is cleaved by caspases into a p68Rb form that still interacts with E2F-1. Moreover, pRb occupies the noxa promoter together with E2F-1, in a caspase-dependent manner upon ABT-737 treatment. Thus, caspases contribute to trigger the mitochondrial apoptotic pathway by coupling Bcl-2/Bcl-xL inhibition to that of Mcl-1, via the pRb/E2F-1-dependent induction of Noxa. Cell Death and Differentiation (2013) 20, 755-764; doi:10.1038/cdd.2013.6; published online 22 February 2013
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