title: p53/TAp63 and AKT regulate mammalian target of rapamycin complex 1 (mTORC1) signaling through two independent parallel pathways in the presence of DNA damage.
abstract: Under conditions of DNA damage, the mammalian target of rapamycin complex 1 (mTORC1) is inhibited, preventing cell cycle progression and conserving cellular energy by suppressing translation. We show that suppression of mTORC1 signaling to 4E-BP1 requires the coordinated activity of two tumor suppressors, p53 and p63. In contrast, suppression of S6K1 and ribosomal protein S6 phosphorylation by DNA damage is Akt-dependent. We find that loss of either p53, required for the induction of Sestrin 1/2, or p63, required for the induction of REDD1 and activation of the tuberous sclerosis complex, prevents the DNA damage-induced suppression of mTORC1 signaling. These data indicate that the negative regulation of cap-dependent translation by mTORC1 inhibition subsequent to DNA damage is abrogated in most human cancers.
authors.affiliation: From the Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio 43205.
authors.forename: Maren
authors.initials: M
authors.lastname: Cam
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Bid
authors.forename: Linlin
authors.initials: L
authors.lastname: Xiao
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Zambetti
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Hakan
authors.initials: H
authors.lastname: Cam
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004249:DNA Damage; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000084622:Sestrins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D006360:Heat-Shock Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C469991:DDIT4 protein, human; C087000:EIF4EBP1 protein, human; C117338:SESN1 protein, human; D000084622:Sestrins; C465398:SESN2 protein, human; C495901:TP53 protein, human; C115051:TP63 protein, human; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1
keywords: 4EBP1; Akt; DNA Damage Response; REDD1; S6K1; Sestrin; mTOR; mTOR Complex (mTORC); p53; p63