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.

• Authors: K Rajesh, J Krishnamoorthy, U Kazimierczak, C Tenkerian, A I Papadakis, S Wang, S Huang, A E Koromilas
• Journal: Cell death & disease (Cell Death Dis) Vol. 6 Pg. e1591 (Jan 15 2015) ISSN: 2041-4889 [Electronic] England
• PMID: 25590801 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Atf4 protein, mouse
• Eukaryotic Initiation Factor-2
• Multiprotein Complexes
• Oxidants
• Activating Transcription Factor 4
• Phosphoserine
• Eif2ak4 protein, mouse
• Mechanistic Target of Rapamycin Complex 1
• PERK kinase
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• eIF-2 Kinase
• Sirolimus

Topics

• Activating Transcription Factor 4 (metabolism)
• Animals
• Cell Death (drug effects)
• Cell Lineage (drug effects)
• Cell Survival (drug effects)
• Enzyme Activation (drug effects)
• Eukaryotic Initiation Factor-2 (deficiency, metabolism)
• Gene Deletion
• Humans
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Models, Biological
• Multiprotein Complexes (metabolism)
• Oxidants (pharmacology)
• Oxidative Stress (drug effects)
• Phosphorylation (drug effects)
• Phosphoserine (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases (metabolism)
• eIF-2 Kinase (metabolism)