Molecular Cell
Volume 44, Issue 4, 18 November 2011, Pages 621-634
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Article
PGC-1α, a Key Modulator of p53, Promotes Cell Survival upon Metabolic Stress

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Summary

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.

Highlights

► PGC-1α serves as p53 coactivator and modulates its target selection ► PGC-1α promotes the cell-cycle arrest and metabolic functions of p53 ► Prolonged starvation results in PGC-1α degradation via ubiquitin-proteasome pathway ► PGC-1α modulates p53-mediated starvation response in vivo

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