p53/TAp63 and AKT Regulate Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling through Two Independent Parallel Pathways in the Presence of DNA Damage |
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| Authors: | Maren Cam Hemant K. Bid Linlin Xiao Gerard P. Zambetti Peter J. Houghton Hakan Cam |
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| Affiliation: | From the ‡Center for Childhood Cancer and Blood Diseases, Nationwide Children''s Hospital, Columbus, Ohio 43205.;the §Department of Biochemistry, St. Jude Children''s Research Hospital, Memphis, Tennessee 38105, and ;the ¶Department of Pediatrics, College of Medicine, Ohio State University, Columbus, Ohio 43205 |
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| 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. |
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| Keywords: | Akt DNA Damage Response mTOR mTOR Complex (mTORC) p53 p63 4EBP1 REDD1 S6K1 Sestrin |
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