Abstract
We show that the mitogen-activated protein kinases ERK1/2 are components of the mechanism by which glucose stimulates insulin gene expression. ERK1/2 activity is required for glucose-dependent transcription from both the full-length rat insulin I promoter and the glucose-sensitive isolated E2A3/4 promoter element in intact islets and beta cell lines. Dominant negative ERK2 and MEK inhibitors suppress glucose stimulation of the rat insulin I promoter and the E2A3/4 element. Overexpression of ERK2 is sufficient to stimulate transcription from the E2A3/4 element. The glucose-induced response is dependent upon ERK1/2 phosphorylation of a subset of transcription factors that include Beta2 (also known as NeuroD1) and PDX-1. Phosphorylation increases their functional activity and results in a cumulative transactivation of the promoter. Thus, ERK1/2 act at multiple points to transduce a glucose signal to insulin gene transcription.
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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Animals
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Blotting, Northern
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Cells, Cultured
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Cricetinae
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Dimerization
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Dose-Response Relationship, Drug
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Female
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Gene Expression Regulation, Enzymologic*
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Genes, Dominant
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Genetic Vectors
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Glucose / metabolism
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Glutathione Transferase / metabolism
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Insulin / metabolism*
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Islets of Langerhans / metabolism*
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Male
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Mice
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism*
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Mutagenesis, Site-Directed
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Phosphorylation
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Promoter Regions, Genetic
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Protein Binding
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Recombinant Proteins / metabolism
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Retroviridae / genetics
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Transcription, Genetic*
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Transcriptional Activation
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Transfection
Substances
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Enzyme Inhibitors
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Insulin
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RNA, Messenger
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Recombinant Proteins
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Glutathione Transferase
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Glucose