title: Analysis of p53 transactivation domain mutants reveals Acad11 as a metabolic target important for p53 pro-survival function.
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.
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Dadi
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Edward L
authors.initials: EL
authors.lastname: LaGory
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kenzelmann Brož
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Kathryn T
authors.initials: KT
authors.lastname: Bieging
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Colleen A
authors.initials: CA
authors.lastname: Brady
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Nichole
authors.initials: N
authors.lastname: Link
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Abrams
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
authors.affiliation: 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.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Attardi
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053263:Gene Regulatory Networks; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D016415:Sequence Alignment; D013312:Stress, Physiological; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; C000603104:ACAD11 protein, human; D042964:Acyl-CoA Dehydrogenase; D005947:Glucose