TY - JOUR
T1 - Regulation of microRNA-375 by cAMP in pancreatic-βcells
AU - Keller, David M.
AU - Clark, Elizabeth A.
AU - Goodman, Richard H.
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
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U2 - 10.1210/me.2011-1205
DO - 10.1210/me.2011-1205
M3 - Article
C2 - 22539037
AN - SCOPUS:84861203551
SN - 0888-8809
VL - 26
SP - 989
EP - 999
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 6
ER -