Downregulation of PERK activity and eIF2 alpha serine 51 phosphorylation by mTOR complex 1 elicits pro-oxidant and pro-death effects in tuberous sclerosis-deficient cells

作者：Krishnamoorthy Jothilatha; Tenkerian Clara; Gupta Jyotsana; Ghaddar Nour; Wang Shuo; Darini Cedric; Staschke Kirk A; Ghosh Abhishek; Gandin Valentina; Topisirovic Ivan; Kristof Arnold S; Hatzoglou Maria; Simos George; Koromilas Antonis E^*

来源：Cell Death & Disease, 2018, 9(3): 254.

DOI：10.1038/s41419-018-0326-2

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 eIF2 alpha at serine 51 (eIF2 alpha P) plays a prominent role. Increased eIF2 alpha P can contribute to tumor progression as well as tumor suppression. While eIF2 alpha P is increased in most cells to promote survival and adaptation to different forms of stress, we demonstrate that eIF2 alpha P is reduced in tuberous sclerosis complex 2 (TSC2)-deficient cells subjected to oxidative insults. Decreased eIF2 alpha P 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 eIF2 alpha P is accompanied by increased ROS production and enhanced susceptibility of TSC2-deficient cells to extrinsic pro-oxidant stress. The decreased levels of eIF2 alpha P 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 eIF2 alpha P in TSC2-deficient cells with potential implications in tumor suppression in response to oxidative insults.

• 出版日期2018-2-15
• 单位河北医科大学; McGill