title: Regulation of microRNA-375 by cAMP in pancreatic β-cells.
abstract: MicroRNA-375 (miR-375) is necessary for proper formation of pancreatic islets in vertebrates and is necessary for the development of β-cells in mice, but regulation of miR-375 in these cells is poorly understood. Here, we show that miR-375 is transcriptionally repressed by the cAMP-protein kinase A (PKA) pathway and that this repression is mediated through a block in RNA polymerase II binding to the miR-375 promoter. cAMP analogs that are PKA selective repress miR-375, as do cAMP agonists and the glucagon-like peptide-1 receptor agonist, exendin-4. Repression of the miR-375 precursor occurs rapidly in rat insulinoma INS-1 832/13 cells, within 15 min after cAMP stimulation, although the mature microRNA declines more slowly due to the kinetics of RNA processing. Repression of miR-375 in isolated rat islets by exendin-4 also occurs slowly, after several hours of stimulation. Glucose is another reported antagonist of miR-375 expression, although we demonstrate here that glucose does not target the microRNA through the PKA pathway. As reported previously, miR-375 negatively regulates insulin secretion, and attenuation of miR-375 through the cAMP-PKA pathway may boost the insulin response in pancreatic β-cells.
authors.affiliation: Department of Biological Sciences, California State University, Chico, CA 95929-0515, USA. dmkeller@csuchico.edu
authors.forename: David M
authors.initials: DM
authors.lastname: Keller
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Clark
authors.forename: Richard H
authors.initials: RH
authors.lastname: Goodman
mesh_terms: D000598:Amino Acids, Cyclic / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D055029:Inverted Repeat Sequences; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014688:Venoms / Q000494:pharmacology
chemical_list: D000598:Amino Acids, Cyclic; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; C574979:MIRN375 microRNA, rat; D035683:MicroRNAs; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose