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Cell Rep. 2015 Feb 24;10(7):1096-109. doi: 10.1016/j.celrep.2015.01.043. Epub 2015 Feb 19.

Analysis of p53 transactivation domain mutants reveals Acad11 as a metabolic target important for p53 pro-survival function.

Author information

1
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: attardi@stanford.edu.

Abstract

The p53 tumor suppressor plays a key role in maintaining cellular integrity. In response to diverse stress signals, p53 can trigger apoptosis to eliminate damaged cells or cell-cycle arrest to enable cells to cope with stress and survive. However, the transcriptional networks underlying p53 pro-survival function are incompletely understood. Here, we show that in oncogenic-Ras-expressing cells, p53 promotes oxidative phosphorylation (OXPHOS) and cell survival upon glucose starvation. Analysis of p53 transcriptional activation domain mutants reveals that these responses depend on p53 transactivation function. Using gene expression profiling and ChIP-seq analysis, we identify several p53-inducible fatty acid metabolism-related genes. One such gene, Acad11, encoding a protein involved in fatty acid oxidation, is required for efficient OXPHOS and cell survival upon glucose starvation. This study provides new mechanistic insight into the pro-survival function of p53 and suggests that targeting this pathway may provide a strategy for therapeutic intervention based on metabolic perturbation.

PMID:
25704813
PMCID:
PMC4365998
DOI:
10.1016/j.celrep.2015.01.043
[Indexed for MEDLINE]
Free PMC Article

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