Abstract17Correspondence should be addressed to G.K. (e-mail: E-mail: kroemer@igr.fr). 16 These authors contributed equally to this paper. AUTHOR 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.Note: Supplementary Information is available on the Nature Cell Biology website. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests. NIH Public Access Author ManuscriptNat Cell Biol. Author manuscript; available in PMC 2009 May 4. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMultiple cellular stressors, including activation of the tumour suppressor p53, can stimulate autophagy. Here we show that knockout, knockdown or pharmacological inhibition of p53 can induce autophagy in human, mouse and nematode cells. 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.Autophagy (`self-eating') is an important eukaryotic response to cellular stress. During autophagy, portions of the cytosol and cytoplasmic organelles are sequestered within characteristic double-or multi-membraned autophagosomes and delivered to lysosomes for bulk degradation. By promoting catabolic reactions, autophagy generates new metabolic substrates that meet the bioenergetic needs of cells and allows for adaptive protein synthesis. Autophagy also constitutes a homeostatic `clean-up' process to rid cells of intracellular parasites, damaged organelles and potentially toxic, aggregate-prone proteins. Finally, autophagy has been viewed as a self-destructive process in which stressed cells succumb to the so-called autophagic cell death 1 .Autophagy is essential for the long-term survival of mammalian cells and a partial reduction in the autophagic capacity may constitute an oncogenic event. At least one of the phylogenetically conserved autophagy genes, atg6/beclin 1, is frequently inactivated at one locus in human cancers, and mouse studies have confirmed that beclin 1 is a haploinsufficient tumour suppressor 2 . There are two non-exclusive hypotheses to explain how inhibition of autoph...
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