Abstract
Protein kinases that phosphorylate the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) are activated in stressed cells and negatively regulate protein synthesis. Phenotypic analysis of targeted mutations in murine cells reveals a novel role for eIF2alpha 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 eIF2alpha 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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Activating Transcription Factor 4
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Amino Acids / biosynthesis
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Amino Acids / deficiency*
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Amino Acids / genetics
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Animals
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CCAAT-Enhancer-Binding Proteins / genetics
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Carrier Proteins / metabolism
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Cell Line
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Cricetinae
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Endoplasmic Reticulum / metabolism
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Endoplasmic Reticulum Chaperone BiP
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Eukaryotic Initiation Factor-2 / chemistry
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Eukaryotic Initiation Factor-2 / metabolism
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Gene Expression Regulation*
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Heat-Shock Proteins*
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Mammals / genetics*
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Mice
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Molecular Chaperones / metabolism
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Mutation / genetics
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Peptide Chain Initiation, Translational*
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Phosphorylation
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Protein Denaturation
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Protein Folding*
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Protein Kinases / genetics
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Ribosomes / metabolism
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Signal Transduction
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Transcription Factor CHOP
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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eIF-2 Kinase / genetics
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eIF-2 Kinase / metabolism*
Substances
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Amino Acids
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Atf4 protein, rat
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CCAAT-Enhancer-Binding Proteins
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Carrier Proteins
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Ddit3 protein, mouse
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Ddit3 protein, rat
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Endoplasmic Reticulum Chaperone BiP
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Eukaryotic Initiation Factor-2
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Heat-Shock Proteins
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Molecular Chaperones
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RNA, Messenger
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Transcription Factors
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Activating Transcription Factor 4
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Transcription Factor CHOP
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Protein Kinases
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Eif2ak4 protein, mouse
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PERK kinase
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Protein Serine-Threonine Kinases
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eIF-2 Kinase