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Downregulation of PERK activity and eIF2α serine 51 phosphorylation by mTOR complex 1 elicits pro-oxidant and pro-death effects in tuberous sclerosis-deficient cells article
dc.creator | Krishnamoorthy J., Tenkerian C., Gupta J., Ghaddar N., Wang S., Darini C., Staschke K.A., Ghosh A., Gandin V., Topisirovic I., Kristof A.S., Hatzoglou M., Simos G., Koromilas A.E. | en |
dc.date.accessioned | 2023-01-31T08:47:08Z | |
dc.date.available | 2023-01-31T08:47:08Z | |
dc.date.issued | 2018 | |
dc.identifier | 10.1038/s41419-018-0326-2 | |
dc.identifier.issn | 20414889 | |
dc.identifier.uri | http://hdl.handle.net/11615/75516 | |
dc.description.abstract | Oxidative stress determines cell fate through several mechanisms, among which regulation of mRNA translation by the phosphorylation of the alpha (α) subunit of the translation initiation factor eIF2α at serine 51 (eIF2αP) plays a prominent role. Increased eIF2αP can contribute to tumor progression as well as tumor suppression. While eIF2αP is increased in most cells to promote survival and adaptation to different forms of stress, we demonstrate that eIF2αP is reduced in tuberous sclerosis complex 2 (TSC2)-deficient cells subjected to oxidative insults. Decreased eIF2αP in TSC2-deficient cells depends on reactive oxygen species (ROS) production and is associated with a reduced activity of the endoplasmic reticulum (ER)-resident kinase PERK owing to the hyper-activation of the mammalian target of rapamycin complex 1 (mTORC1). Downregulation of PERK activity and eIF2αP is accompanied by increased ROS production and enhanced susceptibility of TSC2-deficient cells to extrinsic pro-oxidant stress. The decreased levels of eIF2αP delay tumor formation of TSC2-deficient cells in immune deficient mice, an effect that is significantly alleviated in mice subjected to an anti-oxidant diet. Our findings reveal a previously unidentified connection between mTORC1 and eIF2αP in TSC2-deficient cells with potential implications in tumor suppression in response to oxidative insults. © 2018 The Author(s). | en |
dc.language.iso | en | en |
dc.source | Cell Death and Disease | en |
dc.source.uri | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85042173030&doi=10.1038%2fs41419-018-0326-2&partnerID=40&md5=9a69c028709ddd63ec933397db2b36aa | |
dc.subject | initiation factor 2alpha | en |
dc.subject | initiation factor 2alpha serine 51 | en |
dc.subject | mammalian target of rapamycin complex 1 | en |
dc.subject | oxidizing agent | en |
dc.subject | phosphotransferase | en |
dc.subject | pkr like endoplasmic reticulum resident kinase | en |
dc.subject | reactive oxygen metabolite | en |
dc.subject | tuberin | en |
dc.subject | unclassified drug | en |
dc.subject | antioxidant | en |
dc.subject | initiation factor 2 | en |
dc.subject | mammalian target of rapamycin complex 1 | en |
dc.subject | PERK kinase | en |
dc.subject | protein kinase R | en |
dc.subject | reactive oxygen metabolite | en |
dc.subject | serine | en |
dc.subject | Tsc2 protein, mouse | en |
dc.subject | tuberin | en |
dc.subject | animal cell | en |
dc.subject | animal experiment | en |
dc.subject | animal model | en |
dc.subject | animal tissue | en |
dc.subject | antineoplastic activity | en |
dc.subject | antioxidant activity | en |
dc.subject | Article | en |
dc.subject | cell death | en |
dc.subject | cell stress | en |
dc.subject | cell survival | en |
dc.subject | controlled study | en |
dc.subject | down regulation | en |
dc.subject | embryo | en |
dc.subject | endoplasmic reticulum | en |
dc.subject | enzyme activity | en |
dc.subject | enzyme phosphorylation | en |
dc.subject | female | en |
dc.subject | human | en |
dc.subject | human cell | en |
dc.subject | mouse | en |
dc.subject | nonhuman | en |
dc.subject | oxidative stress | en |
dc.subject | priority journal | en |
dc.subject | SCID beige mouse | en |
dc.subject | tumor xenograft | en |
dc.subject | animal | en |
dc.subject | cell culture | en |
dc.subject | cell death | en |
dc.subject | down regulation | en |
dc.subject | drug effect | en |
dc.subject | enzymology | en |
dc.subject | fibroblast | en |
dc.subject | genetics | en |
dc.subject | metabolism | en |
dc.subject | neoplasm | en |
dc.subject | oxidative stress | en |
dc.subject | pathology | en |
dc.subject | phosphorylation | en |
dc.subject | SCID mouse | en |
dc.subject | signal transduction | en |
dc.subject | time factor | en |
dc.subject | tuberous sclerosis | en |
dc.subject | tumor volume | en |
dc.subject | Animals | en |
dc.subject | Antioxidants | en |
dc.subject | Cell Death | en |
dc.subject | Cells, Cultured | en |
dc.subject | Down-Regulation | en |
dc.subject | eIF-2 Kinase | en |
dc.subject | Eukaryotic Initiation Factor-2 | en |
dc.subject | Female | en |
dc.subject | Fibroblasts | en |
dc.subject | Humans | en |
dc.subject | Mechanistic Target of Rapamycin Complex 1 | en |
dc.subject | Mice | en |
dc.subject | Mice, SCID | en |
dc.subject | Neoplasms | en |
dc.subject | Oxidative Stress | en |
dc.subject | Phosphorylation | en |
dc.subject | Reactive Oxygen Species | en |
dc.subject | Serine | en |
dc.subject | Signal Transduction | en |
dc.subject | Time Factors | en |
dc.subject | Tuberous Sclerosis | en |
dc.subject | Tuberous Sclerosis Complex 2 Protein | en |
dc.subject | Tumor Burden | en |
dc.subject | Nature Publishing Group | en |
dc.title | Downregulation of PERK activity and eIF2α serine 51 phosphorylation by mTOR complex 1 elicits pro-oxidant and pro-death effects in tuberous sclerosis-deficient cells article | en |
dc.type | journalArticle | en |
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