Regulated translation initiation controls stress-induced gene expression in mammalian cells

Protein kinases that phosphorylate the alpha subunit of eukaryotic initiati on factor 2 (eIF2 alpha) are activated in stressed cells and negatively reg ulate protein synthesis. Phenotypic analysis of targeted mutations in murin e cells reveals a novel role for eIF2 alpha kinases in regulating gene expr ession in the unfolded protein response (UPR) and in amino acid starved cel ls. When activated by their cognate upstream stress signals, the mammalian eIF2 kinases PERK and GCN2 repress translation of most mRNAs but selectivel y increase translation of Activating Transcription Factor 4 (ATF4), resulti ng in the induction of the downstream gene CHOP (GADD153). This is the firs t example of a mammalian signaling pathway homologous to the well studied y east general control response in which eIF2 alpha 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.