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J Biol Chem. 2014 Feb 14;289(7):4083-94. doi: 10.1074/jbc.M113.530303. Epub 2013 Dec 23.

p53/TAp63 and AKT regulate mammalian target of rapamycin complex 1 (mTORC1) signaling through two independent parallel pathways in the presence of DNA damage.

Author information

1
From the Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio 43205.

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.

KEYWORDS:

4EBP1; Akt; DNA Damage Response; REDD1; S6K1; Sestrin; mTOR; mTOR Complex (mTORC); p53; p63

PMID:
24366874
PMCID:
PMC3924274
DOI:
10.1074/jbc.M113.530303
[Indexed for MEDLINE]
Free PMC Article

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