title: Mutant p53 protein localized in the cytoplasm inhibits autophagy.
abstract: The knockout, knockdown or chemical inhibition of p53 stimulates autophagy. Moreover, autophagy-inducing stimuli such as nutrient depletion, rapamycin or lithium cause the depletion of cytoplasmic p53, which in turn is required for the induction of autophagy. Here, we show that retransfection of p53(-/-) HCT 116 colon carcinoma cells with wild type p53 decreases autophagy down to baseline levels. Surprisingly, one third among a panel of 22 cancer-associated p53 single amino acid mutants also inhibited autophagy when transfected into p53(-/-) cells. Those variants of p53 that preferentially localize to the cytoplasm effectively repressed autophagy, whereas p53 mutants that display a prominently nuclear distribution failed to inhibit autophagy. The investigation of a series of deletion mutants revealed that removal of the DNA-binding domain from p53 fails to interfere with its role in the regulation of autophagy. Altogether, these results identify the cytoplasmic localization of p53 as the most important feature for p53-mediated autophagy inhibition. Moreover, the structural requirements for the two biological activities of extranuclear p53, namely induction of apoptosis and inhibition of autophagy, are manifestly different.
authors.affiliation: INSERM, U848, Villejuif, France.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Morselli
authors.forename: Ezgi
authors.initials: E
authors.lastname: Tasdemir
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Maiuri
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Galluzzi
authors.forename: Oliver
authors.initials: O
authors.lastname: Kepp
authors.forename: Alfredo
authors.initials: A
authors.lastname: Criollo
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Vicencio
authors.forename: Thierry
authors.initials: T
authors.lastname: Soussi
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D001343:Autophagy / Q000235:genetics*; D003593:Cytoplasm / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D009154:Mutation; D016159:Tumor Suppressor Protein p53 / Q000032:analysis* / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53