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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
- Source :
- Molecular and cellular endocrinology. 424
- Publication Year :
- 2015
-
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.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_specialty
Transcription, Genetic
medicine.medical_treatment
Protein Serine-Threonine Kinases
CREB
Biochemistry
Cell Line
03 medical and health sciences
miR-132
chemistry.chemical_compound
Endocrinology
Internal medicine
Insulin-Secreting Cells
microRNA
Transcriptional regulation
medicine
Gene silencing
Animals
Humans
Phosphorylation
Rats, Wistar
Molecular Biology
Forskolin
biology
Kinase
Insulin
Middle Aged
Cell biology
Rats
MicroRNAs
030104 developmental biology
Glucose
chemistry
Gene Expression Regulation
biology.protein
Female
Transcription Factors
Subjects
Details
- ISSN :
- 18728057
- Volume :
- 424
- Database :
- OpenAIRE
- Journal :
- Molecular and cellular endocrinology
- Accession number :
- edsair.doi.dedup.....177597c9a558e3500c13191f644f3d20