Analysis of p53 Transactivation Domain Mutants Reveals Acad11 as a Metabolic Target Important for p53 Pro-Survival Function

Dadi Jiang, Edward L. LaGory, Daniela KenzelmannBrož, Kathryn T. Bieging, Colleen A. Brady, Nichole Link, John M. Abrams, Amato J. Giaccia, Laura D. Attardi

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The p53 tumor suppressor plays a key role in maintaining cellular integrity. In response to diverse stresssignals, 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 inoncogenic-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.

Original languageEnglish (US)
Pages (from-to)1096-1109
Number of pages14
JournalCell Reports
Volume10
Issue number7
DOIs
StatePublished - Feb 24 2015

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Transcriptional Activation
Oxidative Phosphorylation
Cells
Starvation
Cell Survival
Fatty Acids
Glucose
Gene encoding
Gene Regulatory Networks
Gene Expression Profiling
Cell Cycle Checkpoints
Metabolism
Gene expression
Genes
Tumors
Chemical activation
Apoptosis
Oxidation
Neoplasms
Proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Jiang, D., LaGory, E. L., KenzelmannBrož, D., Bieging, K. T., Brady, C. A., Link, N., ... Attardi, L. D. (2015). Analysis of p53 Transactivation Domain Mutants Reveals Acad11 as a Metabolic Target Important for p53 Pro-Survival Function. Cell Reports, 10(7), 1096-1109. https://doi.org/10.1016/j.celrep.2015.01.043

Analysis of p53 Transactivation Domain Mutants Reveals Acad11 as a Metabolic Target Important for p53 Pro-Survival Function. / Jiang, Dadi; LaGory, Edward L.; KenzelmannBrož, Daniela; Bieging, Kathryn T.; Brady, Colleen A.; Link, Nichole; Abrams, John M.; Giaccia, Amato J.; Attardi, Laura D.

In: Cell Reports, Vol. 10, No. 7, 24.02.2015, p. 1096-1109.

Research output: Contribution to journalArticle

Jiang, D, LaGory, EL, KenzelmannBrož, D, Bieging, KT, Brady, CA, Link, N, Abrams, JM, Giaccia, AJ & Attardi, LD 2015, 'Analysis of p53 Transactivation Domain Mutants Reveals Acad11 as a Metabolic Target Important for p53 Pro-Survival Function', Cell Reports, vol. 10, no. 7, pp. 1096-1109. https://doi.org/10.1016/j.celrep.2015.01.043
Jiang, Dadi ; LaGory, Edward L. ; KenzelmannBrož, Daniela ; Bieging, Kathryn T. ; Brady, Colleen A. ; Link, Nichole ; Abrams, John M. ; Giaccia, Amato J. ; Attardi, Laura D. / Analysis of p53 Transactivation Domain Mutants Reveals Acad11 as a Metabolic Target Important for p53 Pro-Survival Function. In: Cell Reports. 2015 ; Vol. 10, No. 7. pp. 1096-1109.
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