Phosphorylation of the translation initiation factor eIF2α at serine 51 determines the cell fate decisions of Akt in response to oxidative stress

Abstract

Phosphorylation of the α subunit of the translation initiation factor eIF2 at serine 51 (eIF2αP) is a master regulator of cell adaptation to various forms of stress with implications in antitumor treatments with chemotherapeutic drugs. Herein, we demonstrate that genetic loss of the eIF2α kinases PERK and GCN2 or impaired eIF2αP by genetic means renders immortalized mouse fibroblasts as well as human tumor cells increasingly susceptible to death by oxidative stress. We also show that eIF2αP facilitates Akt activation in cells subjected to oxidative insults. However, whereas Akt activation has a pro-survival role in eIF2αP-proficient cells, the lesser amount of activated Akt in eIF2αP-deficient cells promotes death. At the molecular level, we demonstrate that eIF2αP acts through an ATF4-independent mechanism to control Akt activity via the regulation of mTORC1. Specifically, eIF2αP downregulates mTORC1 activity, which in turn relieves the feedback inhibition of PI3K resulting in the upregulation of the mTORC2-Akt arm. Inhibition of mTORC1 by rapamycin restores Akt activity in eIF2αP-deficient cells but renders them highly susceptible to Akt-mediated death by oxidative stress. Our data demonstrate that eIF2αP acts as a molecular switch that dictates either cell survival or death by activated Akt in response to oxidative stress. Hence, we propose that inactivation of eIF2αP may be a suitable approach to unleash the killing power of Akt in tumor cells treated with pro-oxidant drugs.

rAAV8-733-Mediated Gene Transfer of CHIP/Stub-1 Prevents Hippocampal Neuronal Death in Experimental Brain Ischemia

“…9,32 Of particular interest, a report suggests that phosphorylation of eIF2a at serine 51 may control the activation of AKT promoting either cell death or survival in response to oxidative stress. 33 The latter studies are, therefore, compatible with our finding that the overexpression of CHIP inhibited the phosphorylation of eIF2a and of AKT. Altogether, the present data from both in vitro and in vivo models of global cerebral ischemia are consistent with the hypothesis that the overexpression of CHIP is sufficient to prevent neurodegeneration in the hippocampus.…”

Nck1 deficiency improves pancreatic β cell survival to diabetes-relevant stresses by modulating PERK activation and signaling

“…Akt activation in MIN6 cells depleted of Nck1 may result from the inhibition of the mTORC1-dependent negative feedback loop leading to PI3K inhibition since mTORC1 activity was attenuated in these cells. Supporting this, a recent study illustrated an important role for PERK-dependent phosphorylation of eIF2αSer 51 in dictating cell death or survival to oxidative stress by activating Akt [67]. Indeed, it was demonstrated that peIF2αSer 51 has a prosurvival function against oxidative stress by downregulating mTORC1 activity, which then promotes Akt activation.…”

The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress

“…It can be inferred that phosphorylation of eIF2α is a master regulator of cell adaptation to ER stress conditions. It is also a significant checkpoint under which not only global protein translation, but also cell proliferation are blocked [68]. Furthermore, phosphorylated eIF2α has a negative influence on eIF2β functioning and acts as its major inhibitor [69].…”