Regulation of autophagy by cytoplasmic p53. Academic Article uri icon

Overview

abstract

  • Multiple cellular stressors, including activation of the tumour suppressor p53, can stimulate autophagy. Here we show that deletion, depletion or inhibition of p53 can induce autophagy in human, mouse and nematode cells subjected to knockout, knockdown or pharmacological inhibition of p53. Enhanced autophagy improved the survival of p53-deficient cancer cells under conditions of hypoxia and nutrient depletion, allowing them to maintain high ATP levels. Inhibition of p53 led to autophagy in enucleated cells, and cytoplasmic, not nuclear, p53 was able to repress the enhanced autophagy of p53(-/-) cells. Many different inducers of autophagy (for example, starvation, rapamycin and toxins affecting the endoplasmic reticulum) stimulated proteasome-mediated degradation of p53 through a pathway relying on the E3 ubiquitin ligase HDM2. Inhibition of p53 degradation prevented the activation of autophagy in several cell lines, in response to several distinct stimuli. These results provide evidence of a key signalling pathway that links autophagy to the cancer-associated dysregulation of p53.

authors

  • Tasdemir, Ezgi
  • Maiuri, M Chiara
  • Galluzzi, Lorenzo
  • Vitale, Ilio
  • Djavaheri-Mergny, Mojgan
  • D'Amelio, Marcello
  • Criollo, Alfredo
  • Morselli, Eugenia
  • Zhu, Changlian
  • Harper, Francis
  • Nannmark, Ulf
  • Samara, Chrysanthi
  • Pinton, Paolo
  • Vicencio, José Miguel
  • Carnuccio, Rosa
  • Moll, Ute M
  • Madeo, Frank
  • Paterlini-Brechot, Patrizia
  • Rizzuto, Rosario
  • Szabadkai, Gyorgy
  • Pierron, Gérard
  • Blomgren, Klas
  • Tavernarakis, Nektarios
  • Codogno, Patrice
  • Cecconi, Francesco
  • Kroemer, Guido

publication date

  • May 4, 2008

Research

keywords

  • Autophagy
  • Cytoplasm
  • Gene Expression Regulation
  • Genes, p53
  • Tumor Suppressor Protein p53

Identity

PubMed Central ID

  • PMC2676564

Scopus Document Identifier

  • 44649141966

Digital Object Identifier (DOI)

  • 10.1038/ncb1730

PubMed ID

  • 18454141

Additional Document Info

volume

  • 10

issue

  • 6