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Regulation of autophagy by cytoplasmic p53

Nature Cell Biology volume 10, pages 676–687 (2008)Cite this article

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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Figure 1: Induction of autophagic vacuolization by deletion, depletion or inhibition of p53.
Figure 2: PFT-α triggers autophagic vacuolization and has no effect on vacuole-lysosome fusion.
Figure 3: Role of AMPK, p70S6K and mTOR in the p53-mediated modulation of autophagy.
Figure 4: p53 deletion attenuates ATP depletion during glucose deprivation and favours survival under metabolic stress.
Figure 5: Inhibition of autophagy by cytoplasmic p53.
Figure 6: p53 inhibition induces autophagy by ER stress (a–c) WT HCT116 cells were transiently transfected with GFP–LC3, treated with PFT-α for 2, 4 or 6 h and subjected to immunofluorescence staining to observe the colocalization of GFP–LC3+puncta with the ER marker ERp57 (a) or a mitochondrial marker (b).
Figure 7: Induction of autophagy requires p53 degradation mediated by HDM2 and the proteasome.

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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).

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Author notes

  1. Ezgi Tasdemir and M. Chiara Maiuri: These authors contributed equally to this paper.

Authors and 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, Villejuif, 94805, 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, Villejuif, 94805, France

    Ezgi Tasdemir, Lorenzo Galluzzi, Ilio Vitale, Alfredo Criollo, Eugenia Morselli, José Miguel Vicencio & Guido Kroemer

  4. School of Biotechnological Sciences and Department of Experimental Pharmacology, Università degli Studi di Napoli Federico II, Napoli, 80131, 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. Department of Biology, Dulbecco Telethon Institute, University of Tor Vergata and IRCCS Fondazione Santa Lucia, Rome, 00133, Italy

    Marcello D'Amelio & Francesco Cecconi

  7. Department of Pediatric Oncology, Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Göteborg University, The Queen Silvia Children's Hospital, Göteborg, Sweden

    Changlian Zhu & Klas Blomgren

  8. CNRS, FRE 2937, Institut Andre Lwoff, Villejuif, 94801, 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, Ferrara, 44100, 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, Graz, 8010, Austria

    Frank Madeo

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

    Patrizia Paterlini-Brechot & Gyorgy Szabadkai

  15. Department of Physiology, University College London, Gower Street, London, WC1E6BT, UK

    Gyorgy Szabadkai

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  1. Ezgi Tasdemir
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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.

Corresponding author

Correspondence to Guido Kroemer.

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Tasdemir, E., Maiuri, M., Galluzzi, L. et al. Regulation of autophagy by cytoplasmic p53. Nat Cell Biol 10, 676–687 (2008). https://doi.org/10.1038/ncb1730

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