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

Heather P. Harding, Isabel Novoa, Yuhong Zhang, Huiqing Zeng, Ron Wek, Matthieu Schapira, David Ron

Research output: Contribution to journalArticle

2072 Scopus citations


Protein kinases that phosphorylate the alpha subunit of eukaryotic initiation factor 2 (elF2α) are activated in stressed cells and negatively regulate protein synthesis. Phenotypic analysis of targeted mutations in murince cells reveals a novel role for elF2α 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 elF2 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 elF2α 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.

Original languageEnglish (US)
Pages (from-to)1099-1108
Number of pages10
JournalMolecular Cell
Issue number5
StatePublished - Jan 1 2000

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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