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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Cell Cycle Proteins
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Cell Line, Tumor
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DNA Damage*
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism
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Humans
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Mice, Knockout
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism*
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Neoplasms / genetics
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Neoplasms / metabolism*
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Neoplasms / pathology
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Phosphorylation / genetics
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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Ribosomal Protein S6 Kinases, 70-kDa / genetics
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Signal Transduction*
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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DDIT4 protein, human
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EIF4EBP1 protein, human
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Heat-Shock Proteins
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Multiprotein Complexes
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Nuclear Proteins
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Phosphoproteins
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SESN1 protein, human
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SESN2 protein, human
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TP53 protein, human
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TP63 protein, human
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Transcription Factors
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Mechanistic Target of Rapamycin Complex 1
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases
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ribosomal protein S6 kinase, 70kD, polypeptide 1