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.

Autor: Malm HA; 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., Mollet IG; 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., Berggreen C; Lund University Diabetes Centre, Lund University, Protein Phosphorylation Research Unit, Dept. Experimental Medical Science, 221 84 Lund, Sweden., Orho-Melander M; Lund University Diabetes Centre, Lund University, Unit of Diabetes and Cardiovascular Disease, Genetic Epidemiology, Dept. Clinical Sciences in Malmö, 205 02 Malmö, Sweden., Esguerra JL; Lund University Diabetes Centre, Lund University, Unit of Islet Cell Exocytosis, Dept. Clinical Sciences in Malmö, 205 02 Malmö, Sweden., Göransson O; Lund University Diabetes Centre, Lund University, Protein Phosphorylation Research Unit, Dept. Experimental Medical Science, 221 84 Lund, Sweden., Eliasson L; 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.
Jazyk: angličtina
Zdroj: Molecular and cellular endocrinology [Mol Cell Endocrinol] 2016 Mar 15; Vol. 424, pp. 23-33. Date of Electronic Publication: 2016 Jan 13.
DOI: 10.1016/j.mce.2016.01.010
Abstrakt: 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.
(Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)
Databáze: MEDLINE
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