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.

1. INSERM, U848.
2. Institut Gustave Roussy, Paris 11, 94805 Villejuif, France.
3. Université Paris Sud, Paris 11, 94805 Villejuif, France.
4. Università degli Studi di Napoli Federico II, School of Biotechnological Sciences and Department of Experimental Pharmacology, 80131 Napoli, Italy.
5. INSERM U756, Université Paris Sud 11, Faculté de Pharmacie, Châtenay-Malabry, France.
6. Dulbecco Telethon Institute, Department of Biology, University of Tor Vergata and IRCCS Fondazione Santa Lucia, 00133 Rome, Italy.
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.
8. CNRS, FRE 2937, Institut Andre Lwoff, 94801 Villejuif, France;
9. Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Göteborg University, Sweden.
10. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Hellas, Heraklion, Crete, Greece.
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.
12. Department of Pathology, State University of New York at Stony Brook, Stony Brook, NY, USA.
13. Institute of Molecular Biosciences, Universitaetsplatz 2, University of Graz, 8010, Graz, Austria.
14. INSERM U807, University Paris V, Faculty of Medicine, Hospital Necker-Enfants Malades, 75015 Paris, France.
15. Department of Physiology, University College London, Gower Street, WC1E6BT London, UK.
16. These authors contributed equally to this paper.

Correspondence to: Guido Kroemer^1,2,3 e-mail: kroemer@igr.fr

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.

NPG Journals

by Subject Area

• Chemistry

  • Chemistry
  • Drug discovery
  • Biotechnology
  • Materials
  • Methods & Protocols

• Clinical Practice & Research

  • Cancer
  • Cardiovascular medicine
  • Dentistry
  • Endocrinology
  • Gastroenterology & Hepatology
  • Methods & Protocols
  • Pathology & Pathobiology
  • Urology

• Earth & Environment

  • Earth sciences
  • Evolution & Ecology

• Life sciences

  • Biotechnology
  • Cancer
  • Development
  • Drug discovery
  • Evolution & Ecology
  • Genetics
  • Immunology
  • Medical research
  • Methods & Protocols
  • Microbiology
  • Molecular cell biology
  • Neuroscience
  • Pharmacology
  • Systems biology

• Physical sciences

  • Physics
  • Materials

by A - Z Index