| First Author | Krishnamoorthy J | Year | 2018 |
| Journal | Cell Death Dis | Volume | 9 |
| Issue | 3 | Pages | 254 |
| PubMed ID | 29449538 | Mgi Jnum | J:319302 |
| Mgi Id | MGI:6863600 | Doi | 10.1038/s41419-018-0326-2 |
| Citation | Krishnamoorthy J, et al. (2018) Downregulation of PERK activity and eIF2alpha serine 51 phosphorylation by mTOR complex 1 elicits pro-oxidant and pro-death effects in tuberous sclerosis-deficient cells. Cell Death Dis 9(3):254 |
| abstractText | Oxidative stress determines cell fate through several mechanisms, among which regulation of mRNA translation by the phosphorylation of the alpha (alpha) subunit of the translation initiation factor eIF2alpha at serine 51 (eIF2alphaP) plays a prominent role. Increased eIF2alphaP can contribute to tumor progression as well as tumor suppression. While eIF2alphaP is increased in most cells to promote survival and adaptation to different forms of stress, we demonstrate that eIF2alphaP is reduced in tuberous sclerosis complex 2 (TSC2)-deficient cells subjected to oxidative insults. Decreased eIF2alphaP 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 eIF2alphaP is accompanied by increased ROS production and enhanced susceptibility of TSC2-deficient cells to extrinsic pro-oxidant stress. The decreased levels of eIF2alphaP 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 eIF2alphaP in TSC2-deficient cells with potential implications in tumor suppression in response to oxidative insults. |
