title: PGC-1α, a key modulator of p53, promotes cell survival upon metabolic stress.
abstract: Metabolic stress results in p53 activation, which can trigger cell-cycle arrest, ROS clearance, or apoptosis. However, what determines the p53-mediated cell fate decision upon metabolic stress is not very well understood. We show here that PGC-1α binds to p53 and modulates its transactivation function, resulting in preferential transactivation of proarrest and metabolic target genes. Thus glucose starvation results in p53-dependent cell-cycle arrest and ROS clearance, but abrogation of PGC-1α expression results in extensive apoptosis. Additionally, prolonged starvation results in PGC-1α degradation concomitant with induction of apoptosis. We have also identified RNF2, a Polycomb group (PcG) protein, as the cognate E3 ubiquitin ligase. Starvation of mice where PGC-1α expression is abrogated results in loss of p53-mediated ROS clearance, enhanced p53-dependent apoptosis, and consequent severe liver atrophy. These findings provide key insights into the role of PGC-1α in regulating p53-mediated cell fate decisions in response to metabolic stress.
authors.affiliation: Molecular Oncology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Nirmalya
authors.initials: N
authors.lastname: Sen
authors.forename: Yatendra Kumar
authors.initials: YK
authors.lastname: Satija
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Das
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005434:Flow Cytometry; D020868:Gene Silencing / Q000187:drug effects; D005947:Glucose / Q000172:deficiency*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D063150:Polycomb Repressive Complex 1; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological / Q000235:genetics*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D063150:Polycomb Repressive Complex 1; C489842:Rnf2 protein, mouse; D044767:Ubiquitin-Protein Ligases; D005947:Glucose