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.
Research output: Contribution to journal › Article
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.
|Research areas and keywords||
Subject classification (UKÄ) – MANDATORY
|Journal||Molecular and Cellular Endocrinology|
|Early online date||2016 Jan 13|
|Publication status||Published - 2016|
Related research output
Transcriptional regulation of miRNA-212 and miRNA-132 and their fine-tuning function of beta cell insulin secretionMalm, H., 2016, Lund: Lund University, Faculty of Medicine. 75 p.
Research output: Thesis › Doctoral Thesis (compilation)