title: Transcriptional regulation of the miR-212/miR-132 cluster in insulin-secreting β-cells by cAMP-regulated transcriptional co-activator 1 and salt-inducible kinases.
abstract: MicroRNAs are central players in the control of insulin secretion, but their transcriptional regulation is poorly understood. Our aim was to investigate cAMP-mediated transcriptional regulation of the miR-212/miR-132 cluster and involvement of further upstream proteins in insulin secreting β-cells. cAMP induced by forskolin+IBMX or GLP-1 caused increased expression of miR-212/miR-132, and elevated phosphorylation of cAMP-response-element-binding-protein (CREB)/Activating-transcription-factor-1 (ATF1) and Salt-Inducible-Kinases (SIKs). CyclicAMP-Regulated Transcriptional Co-activator-1 (CRTC1) was concomitantly dephosphorylated and translocated to the nucleus. Silencing of miR-212/miR-132 reduced, and overexpression of miR-212 increased, glucose-stimulated insulin secretion. Silencing of CRTC1 expression resulted in decreased insulin secretion and miR-212/miR-132 expression, while silencing or inhibition of SIKs was associated with increased expression of the microRNAs and dephosphorylation of CRTC1. CRTC1 protein levels were reduced after silencing of miR-132, suggesting feed-back regulation. Our data propose cAMP-dependent co-regulation of miR-212/miR-132, in part mediated through SIK-regulated CRTC1, as an important factor for fine-tuned regulation of insulin secretion.
authors.affiliation: Lund University Diabetes Centre, Lund University, Unit of Islet Cell Exocytosis, Dept. Clinical Sciences in Malmö, 205 02 Malmö, Sweden; Lund University Diabetes Centre, Lund University, Unit of Diabetes and Cardiovascular Disease, Genetic Epidemiology, Dept. Clinical Sciences in Malmö, 205 02 Malmö, Sweden.
authors.forename: Helena Anna
authors.initials: HA
authors.lastname: Malm
authors.affiliation: Lund University Diabetes Centre, Lund University, Unit of Islet Cell Exocytosis, Dept. Clinical Sciences in Malmö, 205 02 Malmö, Sweden; Lund University Diabetes Centre, Lund University, Unit of Diabetes and Cardiovascular Disease, Genetic Epidemiology, Dept. Clinical Sciences in Malmö, 205 02 Malmö, Sweden.
authors.forename: Inês G
authors.initials: IG
authors.lastname: Mollet
authors.affiliation: Lund University Diabetes Centre, Lund University, Protein Phosphorylation Research Unit, Dept. Experimental Medical Science, 221 84 Lund, Sweden.
authors.forename: Christine
authors.initials: C
authors.lastname: Berggreen
authors.affiliation: Lund University Diabetes Centre, Lund University, Unit of Diabetes and Cardiovascular Disease, Genetic Epidemiology, Dept. Clinical Sciences in Malmö, 205 02 Malmö, Sweden.
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.affiliation: Lund University Diabetes Centre, Lund University, Unit of Islet Cell Exocytosis, Dept. Clinical Sciences in Malmö, 205 02 Malmö, Sweden.
authors.forename: Jonathan Lou S
authors.initials: JL
authors.lastname: Esguerra
authors.affiliation: Lund University Diabetes Centre, Lund University, Protein Phosphorylation Research Unit, Dept. Experimental Medical Science, 221 84 Lund, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Göransson
authors.affiliation: Lund University Diabetes Centre, Lund University, Unit of Islet Cell Exocytosis, Dept. Clinical Sciences in Malmö, 205 02 Malmö, Sweden. Electronic address: lena.eliasson@med.lu.se.
authors.forename: Lena
authors.initials: L
authors.lastname: Eliasson
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C519510:Crtc1 protein, rat; C548821:MIRN132 microRNA, rat; C552427:MIRN212 microRNA, rat; D035683:MicroRNAs; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; D005947:Glucose
keywords: Beta cell; Diabetes; Insulin secretion; Transcription; cAMP; microRNA