p53/TAp63 and AKT Regulate Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling through Two Independent Parallel Pathways in the Presence of DNA Damage
| Autor: | Peter J. Houghton, Hakan Cam, Maren Cam, Hemant K. Bid, Linlin Xiao, Gerard P. Zambetti |
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| Rok vydání: | 2014 |
| Předmět: |
p53
DNA damage mTOR Complex (mTORC) Cell Cycle Proteins P70-S6 Kinase 1 mTORC1 Mechanistic Target of Rapamycin Complex 1 Biology Biochemistry Mice Cell Line Tumor Neoplasms Animals Humans Phosphorylation Molecular Biology Transcription factor Heat-Shock Proteins PI3K/AKT/mTOR pathway Adaptor Proteins Signal Transducing Sestrin Mice Knockout p63 4EBP1 Akt TOR Serine-Threonine Kinases Tumor Suppressor Proteins REDD1 Nuclear Proteins Ribosomal Protein S6 Kinases 70-kDa S6K1 Cell Biology Phosphoproteins Cell biology Multiprotein Complexes Ribosomal protein s6 mTOR DNA Damage Response Tumor Suppressor Protein p53 biological phenomena cell phenomena and immunity Proto-Oncogene Proteins c-akt DNA Damage Signal Transduction Transcription Factors |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m113.530303 |
| Popis: | Background: mTORC1 integrates cellular inputs and is often deregulated in cancer. Results: In response to DNA damage, p53/TAp63 and AKT regulate mTORC1 through two independent parallel pathways. Conclusion: DNA damage activates Akt, resulting in inhibition of S6K1, whereas Sestrin1/2 downstream of p53 and REDD1 downstream of p63 coordinate to suppress 4E-BP1. Significance: mTORC1-dependent 4EBP1 inhibition by DNA damage is abrogated in most human cancers. 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. |
| Databáze: | OpenAIRE |
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