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Cell Cycle. 2015;14(1):56-63. doi: 10.4161/15384101.2014.973330.

ATM regulates cell fate choice upon p53 activation by modulating mitochondrial turnover and ROS levels.

Author information

1
a Howard Hughes Medical Institute and Department of Molecular; Cellular and Developmental Biology ; University of Colorado ; Boulder , CO USA.

Abstract

Despite extensive study, the mechanisms of cell fate choice upon p53 activation remain poorly understood. Using genome-wide shRNA screening, we recently identified the ATM kinase as synthetic lethal with Nutlin-3, an MDM2 inhibitor that leads to non-genotoxic p53 activation. Here, we demonstrate that while this synthetic lethal interaction relies upon components of both the intrinsic and extrinsic apoptotic pathways (e.g., BAX and BID), it is not due to significant ATM effects on the expression of p53 target genes. Instead, loss of ATM activity results in increased mitochondria and reactive oxygen species that drive apoptosis. Finally, we provide evidence that pharmacologic inhibition of ATM blocks autophagy in direct opposition to p53, which activates this process, and that inhibition of autophagy is sufficient to elicit an apoptotic response when combined with Nutlin-3.

KEYWORDS:

ATM; Nutlin-3; ROS; apoptosis; autophagy; mitochondria; p53; reactive oxygen species

PMID:
25483068
PMCID:
PMC4614823
DOI:
10.4161/15384101.2014.973330
[Indexed for MEDLINE]
Free PMC Article

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