Abstract
The accumulation of unfolded protein in the endoplasmic reticulum (ER) attenuates protein synthesis initiation through phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) at Ser51. Subsequently, transcription of genes encoding adaptive functions including the glucose-regulated proteins is induced. We show that eIF2alpha phosphorylation is required for translation attenuation, transcriptional induction, and survival in response to ER stress. Mice with a homozygous mutation at the eIF2alpha phosphorylation site (Ser51Ala) died within 18 hr after birth due to hypoglycemia associated with defective gluconeogenesis. In addition, homozygous mutant embryos and neonates displayed a deficiency in pancreatic beta cells. The results demonstrate that regulation of translation through eIF2alpha phosphorylation is essential for the ER stress response and in vivo glucose homeostasis.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Activating Transcription Factors
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Animals
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Animals, Newborn
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Blood Proteins / genetics
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Blood Proteins / metabolism
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CCAAT-Enhancer-Binding Proteins / genetics
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CCAAT-Enhancer-Binding Proteins / metabolism
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Survival / physiology
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Endoplasmic Reticulum / metabolism
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Endoplasmic Reticulum Chaperone BiP
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Gene Expression / physiology
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Germ-Line Mutation
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Gluconeogenesis / physiology
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Glucose / metabolism*
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Heat-Shock Proteins*
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Homeostasis / physiology*
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Homozygote
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Hypoglycemia / genetics
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Hypoglycemia / metabolism*
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Islets of Langerhans / cytology
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Islets of Langerhans / metabolism
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Mice
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Mice, Mutant Strains
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Molecular Chaperones / genetics
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Molecular Chaperones / metabolism
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Mutagenesis / physiology
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Phosphorylation
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Protein Biosynthesis / physiology*
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Protein Folding
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RNA, Messenger / analysis
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Transcription Factor CHOP
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Transcription Factors / chemistry
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Transcriptional Activation / physiology
Substances
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Activating Transcription Factors
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Blood Proteins
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CCAAT-Enhancer-Binding Proteins
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Carrier Proteins
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DNA-Binding Proteins
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Ddit3 protein, mouse
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Endoplasmic Reticulum Chaperone BiP
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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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Transcription Factor CHOP
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Glucose