Regulation of autophagy by cytoplasmic p53

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)676-687
Number of pages12
JournalNature Cell Biology
Volume10
Issue number6
DOIs
Publication statusPublished - Jun 2008

ASJC Scopus subject areas

  • Cell Biology

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    Tasdemir, E., Maiuri, M. C., Galluzzi, L., Vitale, I., Djavaheri-Mergny, M., D'Amelio, M., Criollo, A., Morselli, E., Zhu, C., Harper, F., Nannmark, U., Samara, C., Pinton, P., Vicencio, J. M., Carnuccio, R., Moll, U. M., Madeo, F., Paterlini-Brechot, P., Rizzuto, R., ... Kroemer, G. (2008). Regulation of autophagy by cytoplasmic p53. Nature Cell Biology, 10(6), 676-687. https://doi.org/10.1038/ncb1730