Regulation of insulin gene transcription by ERK1 and ERK2 in pancreatic beta cells.
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.
Khoo
Shih
S
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Griffen
Steven C
SC
Xia
Ying
Y
Baer
Richard J
RJ
German
Michael S
MS
Cobb
Melanie H
MH
D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D006224:Cricetinae; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005799:Genes, Dominant; D005822:Genetic Vectors; D005947:Glucose / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D004791:Enzyme Inhibitors; D007328:Insulin; D012333:RNA, Messenger; D011994:Recombinant Proteins; D005982:Glutathione Transferase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose