Abstract
Insulin plays a crucial role in the regulation of glucose-homeostasis, and its synthesis is regulated by several stimuli. The transcription of the human insulin gene, enhanced by an elevated intracellular concentration of calcium ions, was completely blocked by Ca2+/calmodulin-dependent protein kinase inhibitor. The activity of the transcription factor activating transcription factor-2 (ATF-2), which binds to the cAMP responsive elements of the human insulin gene, was enhanced by Ca2+/calmodulin-dependent protein kinase IV (CaMKIV). Mutagenesis studies showed that Thr69, Thr71, and Thr73 of ATF-2 are all required for activation by CaMKIV. CaMKIV-induced ATF-2 transcriptional activity was not altered by activation of cJun NH2-terminal protein kinase (JNK) or p38 mitogen-activated protein (MAP) kinase. Furthermore, when transfected into rat primary cultured islets, ATF-2 enhanced glucose-induced insulin promoter activity, whereas cAMP response element-binding protein (CREB) repressed it. These results suggest a mechanism in which ATF-2 regulates insulin gene expression in pancreatic beta-cells, with the transcriptional activity of ATF-2 being increased by an elevated concentration of calcium ions.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 2
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Amino Acid Substitution
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Animals
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Calcium-Calmodulin-Dependent Protein Kinase Type 4
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Line
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Cricetinae
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Cyclic AMP Response Element-Binding Protein / chemistry
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism*
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Gene Expression Regulation* / drug effects
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Glucose / pharmacology
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Humans
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Insulin / genetics*
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Islets of Langerhans / metabolism*
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Luciferases / genetics
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Male
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Mice
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Mutagenesis, Site-Directed
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Promoter Regions, Genetic / drug effects
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Rats
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Rats, Wistar
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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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
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Transfection
Substances
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ATF2 protein, human
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Activating Transcription Factor 2
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Atf2 protein, mouse
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Atf2 protein, rat
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Cyclic AMP Response Element-Binding Protein
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Insulin
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Recombinant Proteins
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Transcription Factors
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Luciferases
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CAMK4 protein, human
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Calcium-Calmodulin-Dependent Protein Kinase Type 4
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Calcium-Calmodulin-Dependent Protein Kinases
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Camk4 protein, mouse
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Camk4 protein, rat
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Glucose