MicroRNA-30d induces insulin transcription factor MafA and insulin production by targeting mitogen-activated protein 4 kinase 4 (MAP4K4) in pancreatic β-cells.
MicroRNAs (miRNAs) represent small noncoding RNAs that play a role in many diseases, including diabetes. miRNAs target genes important for pancreas development, β-cell proliferation, insulin secretion, and exocytosis. Previously, we documented that microRNA-30d (miR-30d), one of miRNAs up-regulated by glucose, induces insulin gene expression in pancreatic β-cells. Here, we found that the induction of insulin production by overexpression of miR-30d is associated with increased expression of MafA, a β-cell-specific transcription factor. Of interest, overexpression of miR-30d prevented the reduction in both MafA and insulin receptor substrate 2 (IRS2) with TNF-α exposure. Moreover, we identified that mitogen-activated protein 4 kinase 4 (MAP4K4), a TNF-α-activated kinase, is a direct target of miR-30d. Overexpression of miR-30d protected β-cells against TNF-α suppression on both insulin transcription and insulin secretion through the down-regulation of MAP4K4 by the miR-30d. A decrease of miR-30d expression was observed in the islets of diabetic db/db mice, in which MAP4K4 expression level was elevated. Our data support the notion that miR-30d plays multiple roles in activating insulin transcription and protecting β-cell functions from impaired by proinflammatory cytokines and underscore the concept that miR-30d may represent a novel pharmacological target for diabetes intervention.
College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China.
Xiaomin
X
Zhao
Ramkumar
R
Mohan
Sabire
S
Özcan
Xiaoqing
X
Tang
D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D015536:Down-Regulation / Q000235:genetics; D005089:Exocytosis; D006801:Humans; D007328:Insulin / Q000096:biosynthesis* / Q000235:genetics; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051473:Maf Transcription Factors, Large / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D051473:Maf Transcription Factors, Large; D035683:MicroRNAs; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase; C526298:Irs2 protein, mouse; C485160:Mafa protein, mouse; C534715:Mirn30d microRNA, mouse