Molecular Cell
Volume 6, Issue 5, November 2000, Pages 1099-1108
Journal home page for Molecular Cell

Article
Regulated Translation Initiation Controls Stress-Induced Gene Expression in Mammalian Cells

https://doi.org/10.1016/S1097-2765(00)00108-8Get rights and content
Under a Creative Commons license
open archive

Abstract

Protein kinases that phosphorylate the alpha subunit of eukaryotic initiation factor 2 (eIF2α) are activated in stressed cells and negatively regulate protein synthesis. Phenotypic analysis of targeted mutations in murine cells reveals a novel role for eIF2α kinases in regulating gene expression in the unfolded protein response (UPR) and in amino acid starved cells. When activated by their cognate upstream stress signals, the mammalian eIF2 kinases PERK and GCN2 repress translation of most mRNAs but selectively increase translation of Activating Transcription Factor 4 (ATF4), resulting in the induction of the downstream gene CHOP (GADD153). This is the first example of a mammalian signaling pathway homologous to the well studied yeast general control response in which eIF2α phosphorylation activates genes involved in amino acid biosynthesis. Mammalian cells thus utilize an ancient pathway to regulate gene expression in response to diverse stress signals.

Cited by (0)