A dual role of p53 in the control of autophagy

Ezgi Tasdemir, M. Chiara Maiuri, Eugenia Morselli, Alfredo Criollo, Marcello D'Amelio, Mojgan Djavaheri-Mergny, Francesco Cecconi, Nektarios Tavernarakis, Guido Kroemer

Research output: Contribution to journalArticlepeer-review

Abstract

Genotoxic stress can induce autophagy in a p53-dependent fashion and p53 can transactivate autophagy-inducing genes. We have observed recently that inactivation of p53 by deletion, depletion or inhibition can trigger autophagy. Thus, human and mouse cells subjected to knockout, knockdown or pharmacological inhibition of p53 manifest signs of autophagy such as depletion of p62/SQSTM1, LC3 lipidation, redistribution of GFP-LC3 in cytoplasmic puncta, and accumulation of autophagosomes and autolysosomes, both in vitro and in vivo. Inhibition of p53 causes autophagy in enucleated cells, indicating that the cytoplasmic, non-nuclear pool of p53 can regulate autophagy. Accordingly, retransfection of p53-/- cells with wild-type p53 as well as a p53 mutant that is excluded from the nucleus (due to the deletion of the nuclear localization sequence) can inhibit autophagy, whereas retransfection with a nucleus-restricted p53 mutant (in which the nuclear localization sequence has been deleted) does not inhibit autophagy. Several distinct autophagy inducers (e.g., starvation, rapamycin, lithium, tunicamycin and thapsigargin) stimulate the rapid degradation of p53. In these conditions, inhibition of the p53-specific E3 ubiquitin ligase HDM2 can avoid p53 depletion and simultaneously prevent the activation of autophagy. Moreover, a p53 mutant that lacks the HDM2 ubiquitinylation site and hence is more stable than wild-type p53 is particularly efficient in suppressing autophagy. In conclusion, p53 plays a dual role in the control of autophagy. On the one hand, nuclear p53 can induce autophagy through transcriptional effects. On the ther hand, cytoplasmic p53 may act as a master repressor of autophagy.

Original languageEnglish
Pages (from-to)810-814
Number of pages5
JournalAutophagy
Volume4
Issue number6
Publication statusPublished - Aug 16 2008

Keywords

  • Apoptosis
  • DNA damage
  • ER stress
  • HDM2
  • Nutrient stress

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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