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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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References

  1. Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Levine, B. & Yuan, J. Autophagy in cell death: an innocent convict? J. Clin. Invest. 115, 2679–2688 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Degenhardt, K. et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10, 51–64 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Qu, X. et al. Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 128, 931–946 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Matthew, R., Karantza-Wadsworth, V. & White, E. Role of autophagy in cancer. Nature Rev. Cancer 7, 961–967 (2007).

    Article  Google Scholar 

  6. Kroemer, G. & Jaattela, M. Lysosomes and autophagy in cell death control. Nature Rev. Cancer 5, 886–897 (2005).

    Article  CAS  Google Scholar 

  7. Boya, P. et al. Inhibition of macroautophagy triggers apoptosis. Mol. Cell Biol. 25, 1025–1040 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Maiuri, C., Zalckvar, E., Kimchi, A. & Kroemer, G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nature Rev. Mol. Cell Biol. 8, 741–752 (2007).

    Article  CAS  Google Scholar 

  9. Vousden, K. H. & Lane, D. P. p53 in health and disease. Nature Rev. Mol. Cell Biol. 8, 275–283 (2007).

    Article  CAS  Google Scholar 

  10. Feng, Z., Zhang, H., Levine, A. J. & Jin, S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc. Natl Acad. Sci. USA 102, 8204–8209 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Martins, C. P., Brown-Swigart, L. & Evan, G. I. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127, 1323–1334 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Amaravadi, R. K. et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Invest. 117, 326–336 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Crighton, D. et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126, 121–134 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Bunz, F. et al. Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J. Clin. Invest. 104, 263–269 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Komarov, P. G. et al. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 285, 1733–1737 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Klionsky, D. J. & al., e. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4, 151–175 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T. & Ohsumi, Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15, 1101–1111 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Criollo, A. et al. Regulation of autophagy by the inositol trisphosphate receptor. Cell Death Differ. 14, 1029–1039 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Liang, X. H. et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672–676 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Mizushima, N. & Yoshimori, T. How to Interpret LC3 Immunoblotting. Autophagy 3 (2007).

  22. Meley, D. et al. AMP-activated protein kinase and the regulation of autophagic proteolysis. J. Biol. Chem. 281, 34870–34879 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Faivre, S., Kroemer, G. & Raymond, E. Current development of mTOR inhibitors as anticancer agents. Nature Rev. Drug Discov. 5, 671–688 (2006).

    Article  CAS  Google Scholar 

  24. Lum, J. J., DeBerardinis, R. J. & Thompson, C. B. Autophagy in metazoans: cell survival in the land of plenty. Natue Rev. Mol. Cell Biol. 6, 439–448 (2005).

    Article  CAS  Google Scholar 

  25. Talos, F., Petrenko, O., Mena, P. & Moll, U. M. Mitochondrially targeted p53 has tumor suppressor activities in vivo. Cancer Res. 65, 9971–9981 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Baker, S. J. et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244, 217–221 (1989).

    Article  CAS  PubMed  Google Scholar 

  27. Tomita, Y. et al. WT p53, but not tumor-derived mutants, bind to Bcl2 via the DNA binding domain and induce mitochondrial permeabilization. J. Biol. Chem. 281, 8600–8606 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Vater, C. A., Bartle, L. M., Dionne, C. A., Littlewood, T. D. & Goldmacher, V. S. Induction of apoptosis by tamoxifen-activation of a p53-estrogen receptor fusion protein expressed in E1A and T24 H-ras transformed p53−/− mouse embryo fibroblasts. Oncogene 13, 739–748 (1996).

    CAS  PubMed  Google Scholar 

  29. Ogata, M. et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell Biol. 26, 9220–9231 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Qu, L. et al. Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3beta. Genes Dev. 18, 261–277 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pluquet, O., Qu, L. K., Baltzis, D. & Koromilas, A. E. Endoplasmic reticulum stress accelerates p53 degradation by the cooperative actions of Hdm2 and glycogen synthase kinase 3β. Mol. Cell Biol. 25, 9392–9405 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yorimitsu, T., Nair, U., Yang, Z. & Klionsky, D. J. Endoplasmic reticulum stress triggers autophagy. J. Biol. Chem. 281, 30299–30304 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Vassilev, L. T. et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844–848 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Issaeva, N. et al. Small molecule RITA binds to p53, blocks p53–HDM-2 interaction and activates p53 function in tumors. Nature Med. 10, 1321–1328 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Kubbutat, M. H., Jones, S. N. & Vousden, K. H. Regulation of p53 stability by Mdm2. Nature 387, 299–303 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Mihara, M. et al. p53 has a direct apoptogenic role at the mitochondria. Mol. Cell 11, 577–590 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Chipuk, J. E., Maurer, U., Green, D. R. & Schuler, M. Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription. Cancer Cell 4, 371–381 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Chipuk, J. E. et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303, 1010–1014 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Pattingre, S. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927–939 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Leu, J. I., Dumont, P., Hafey, M., Murphy, M. E. & George, D. L. Mitochondrial p53 activates Bak and causes disruption of a Bak–Mcl1 complex. Nature Cell Biol. 6, 443–450 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Maiuri, M. C. et al. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J. 26, 2527–2539 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Feng, Z. et al. The regulation of AMPK β1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1–AKT–mTOR pathways. Cancer Res. 67, 3043–3053 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Fabbro, M. & Henderson, B. R. Regulation of tumor suppressors by nuclear-cytoplasmic shuttling. Exp. Cell Res. 282, 59–69 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Toledo, F. & Wahl, G. M. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nature Rev. Cancer 6, 909–923 (2006).

    Article  CAS  Google Scholar 

  45. Lim, Y. P. et al. The p53 knowledgebase: an integrated information resource for p53 research. Oncogene 26, 1517–1521 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Jones, R. G. et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283–293 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Rubinsztein, D. C., Gestwicki, J. E., Murphy, L. O. & Klionsky, D. J. Potential therapeutic applications of autophagy. Nature Rev. Drug Discov. 6, 304–312 (2007).

    Article  CAS  Google Scholar 

  48. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Brahimi-Horn, M. C., Chiche, J. & Pouyssegur, J. Hypoxia signalling controls metabolic demand. Curr. Opin. Cell Biol. 19, 223–229 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720–572 8 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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