title: p53 inhibits autophagy by interacting with the human ortholog of yeast Atg17, RB1CC1/FIP200.
abstract: The tumor suppressor protein p53 tonically suppresses autophagy when it is present in the cytoplasm. This effect is phylogenetically conserved from mammals to nematodes, and human p53 can inhibit autophagy in yeast, as we show here. Bioinformatic investigations of the p53 interactome in relationship to the autophagy-relevant protein network underscored the possible relevance of a direct molecular interaction between p53 and the mammalian ortholog of the essential yeast autophagy protein Atg17, namely RB1-inducible coiled-coil protein 1 (RB1CC1), also called FAK family kinase-interacting protein of 200 KDa (FIP200). Mutational analyses revealed that a single point mutation in p53 (K382R) abolished its capacity to inhibit autophagy upon transfection into p53-deficient human colon cancer or yeast cells. In conditions in which wild-type p53 co-immunoprecipitated with RB1CC1/FIP200, p53 (K382R) failed to do so, underscoring the importance of the physical interaction between these proteins for the control of autophagy. In conclusion, p53 regulates autophagy through a direct molecular interaction with RB1CC1/FIP200, a protein that is essential for the very apical step of autophagy initiation.
authors.affiliation: INSERM, U848, Paris, France.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Morselli
authors.forename: Shensi
authors.initials: S
authors.lastname: Shen
authors.forename: Christoph
authors.initials: C
authors.lastname: Ruckenstuhl
authors.forename: Maria Anna
authors.initials: MA
authors.lastname: Bauer
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mariño
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Galluzzi
authors.forename: Alfredo
authors.initials: A
authors.lastname: Criollo
authors.forename: Mickael
authors.initials: M
authors.lastname: Michaud
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Maiuri
authors.forename: Tokuhiro
authors.initials: T
authors.lastname: Chano
authors.forename: Frank
authors.initials: F
authors.lastname: Madeo
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D001343:Autophagy; D000071183:Autophagy-Related Proteins; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017354:Point Mutation / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000071183:Autophagy-Related Proteins; C407704:RB1CC1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011505:Protein-Tyrosine Kinases