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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.

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Acknowledgements

We thank N. Mizushima for GFP–LC3-transgenic mice, Levine and B. Vogelstein for cell lines, J. Chipuk, C. G. Maki, M. Oren and K. Vousden for mutant p53 plasmids, E. Zaharioudaki, B. Gardie-Capdeville, C. Ladrou, M.R. Duchen, A. Jalil, F. Fanelli and A. Petrini for expert assistance. The cep-1(gk138) mutant strain (TJ1) was provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR). N.T. is funded by EMBO and the EU Sixth Framework Programme. F.C. is funded by Fondazione Telethon, AIRC, Compagnia di San Paolo and the Italian Ministry of Health. E.T. is a recipient of a PhD fellowship from Institut National contre le Cancer (INCa). G.K. is supported by Ligue Nationale contre le Cancer, Agence Nationale pour la Recherche, Cancéropôle Ile-de-France, INCa, Fondation pour la Recherche Médicale, and European Union (Active p53, Apo-Sys, ApopTrain, ChemoRes, TransDeath, RIGHT).

Author information

Author notes

    • Ezgi Tasdemir
    •  & M. Chiara Maiuri

    These authors contributed equally to this paper.

Affiliations

  1. INSERM, U848.

    • Ezgi Tasdemir
    • , M. Chiara Maiuri
    • , Lorenzo Galluzzi
    • , Ilio Vitale
    • , Alfredo Criollo
    • , Eugenia Morselli
    • , José Miguel Vicencio
    •  & Guido Kroemer
  2. Institut Gustave Roussy, Paris 11, 94805 Villejuif, France.

    • Ezgi Tasdemir
    • , M. Chiara Maiuri
    • , Lorenzo Galluzzi
    • , Ilio Vitale
    • , Alfredo Criollo
    • , Eugenia Morselli
    • , José Miguel Vicencio
    •  & Guido Kroemer
  3. Université Paris Sud, Paris 11, 94805 Villejuif, France.

    • Ezgi Tasdemir
    • , Lorenzo Galluzzi
    • , Ilio Vitale
    • , Alfredo Criollo
    • , Eugenia Morselli
    • , José Miguel Vicencio
    •  & Guido Kroemer
  4. Università degli Studi di Napoli Federico II, School of Biotechnological Sciences and Department of Experimental Pharmacology, 80131 Napoli, Italy.

    • M. Chiara Maiuri
    •  & Rosa Carnuccio
  5. INSERM U756, Université Paris Sud 11, Faculté de Pharmacie, Châtenay-Malabry, France.

    • Mojgan Djavaheri-Mergny
    •  & Patrice Codogno
  6. Dulbecco Telethon Institute, Department of Biology, University of Tor Vergata and IRCCS Fondazione Santa Lucia, 00133 Rome, Italy.

    • Marcello D'Amelio
    •  & Francesco Cecconi
  7. Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Göteborg University, Department of Pediatric Oncology, The Queen Silvia Children's Hospital, Göteborg, Sweden.

    • Changlian Zhu
    •  & Klas Blomgren
  8. CNRS, FRE 2937, Institut Andre Lwoff, 94801 Villejuif, France;

    • Francis Harper
    •  & Gérard Pierron
  9. Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Göteborg University, Sweden.

    • Ulf Nannmark
  10. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Hellas, Heraklion, Crete, Greece.

    • Chrysanthi Samara
    •  & Nektarios Tavernarakis
  11. Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI), University of Ferrara, 44100 Ferrara, Italy.

    • Paolo Pinton
    •  & Rosario Rizzuto
  12. Department of Pathology, State University of New York at Stony Brook, Stony Brook, NY, USA.

    • Ute M. Moll
  13. Institute of Molecular Biosciences, Universitaetsplatz 2, University of Graz, 8010, Graz, Austria.

    • Frank Madeo
  14. INSERM U807, University Paris V, Faculty of Medicine, Hospital Necker-Enfants Malades, 75015 Paris, France.

    • Patrizia Paterlini-Brechot
    •  & Gyorgy Szabadkai
  15. Department of Physiology, University College London, Gower Street, WC1E6BT London, UK.

    • Gyorgy Szabadkai

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Contributions

E.T., M.C.M., L.G. and I.V. conducted experiments, prepared figures and analysed data; M.D.-M., M.D.'A., A.C., E.M., C.Z., F.H., U.N., C.S., P.P., J.M.V, R.C., F.M., P.P.B, G.S., G.P., K.B., N.T., P.C. and F.C. performed experiments; E.T. and G.K. planned the project; G.K. supervised the project and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Guido Kroemer.

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DOI

https://doi.org/10.1038/ncb1730

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