p53: The Janus of autophagy?

Abstract

The autophagy pathway functions in adaptation to nutrient stress and tumour suppression. The p53 tumour suppressor, previously thought to positively regulate autophagy, may also inhibit it. This dual interplay between p53 and autophagy regulation is enigmatic, but may underlie key aspects of metabolism and cancer biology.

Figure 1

Models for positive (a) and negative (b) regulation of autophagy by p53. (a) Onocogenic and genotoxic stress result in p53 stabilization and activation, which is believed to stimulate autophagy through both transcription-independent mechanisms (for example, AMPK activation, mTOR inhibition) and transcription-dependent mechanisms (for example, PTEN, TSC1 and DRAM transcriptional upregulation). (b) Genetic or chemical inhibition of p53 (not depicted here), or proteasomal depletion of p53 during starvation and ER stress, activates autophagy through transcription-independent mechanisms involving AMPK activation and mTOR inhibition. P53 loss also leads to ER stress-induced autophagy. Dotted lines represent a speculative pathway by which p53 depletion may also result in autophagy. p53 loss leads to homeostatic imbalance (for example, bioenergetic compromise, reactive oxygen species, defective cell-cycle checkpoints), which leads to autophagy; therefore, p53 depletion may induce autophagy indirectly through homeostatic imbalance.