Abstract
Eukaryotic cells respond to unfolded proteins in their endoplasmic reticulum (ER stress), amino acid starvation, or oxidants by phosphorylating the alpha subunit of translation initiation factor 2 (eIF2alpha). This adaptation inhibits general protein synthesis while promoting translation and expression of the transcription factor ATF4. Atf4(-/-) cells are impaired in expressing genes involved in amino acid import, glutathione biosynthesis, and resistance to oxidative stress. Perk(-/-) cells, lacking an upstream ER stress-activated eIF2alpha kinase that activates Atf4, accumulate endogenous peroxides during ER stress, whereas interference with the ER oxidase ERO1 abrogates such accumulation. A signaling pathway initiated by eIF2alpha phosphorylation protects cells against metabolic consequences of ER oxidation by promoting the linked processes of amino acid sufficiency and resistance to oxidative stress.
Publication types
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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 / metabolism*
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Animals
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Anti-Bacterial Agents / pharmacology
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Blotting, Northern
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Caenorhabditis elegans
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Cell Division
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Cell Separation
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Cytochrome c Group / metabolism
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Dose-Response Relationship, Drug
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Endoplasmic Reticulum / metabolism
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Eukaryotic Initiation Factor-2 / chemistry
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Eukaryotic Initiation Factor-2 / metabolism*
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Fibroblasts / metabolism
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Flow Cytometry
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Genotype
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Glutathione / metabolism
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Immunoblotting
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Mice
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Microscopy, Fluorescence
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Mutation
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Oxidative Stress*
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Peroxidase / metabolism
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Phosphorylation
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Precipitin Tests
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Time Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tunicamycin / pharmacology
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Up-Regulation
Substances
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Amino Acids
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Anti-Bacterial Agents
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Cytochrome c Group
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Eukaryotic Initiation Factor-2
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Transcription Factors
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Tunicamycin
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Activating Transcription Factor 4
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Peroxidase
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Glutathione