MicroRNA-30d Induces Insulin Transcription Factor MafA and Insulin Production by Targeting Mitogen-activated Protein 4 Kinase 4 (MAP4K4) in Pancreatic β-Cells

• Published in: The Journal of biological chemistry 2012-09, Vol.287 (37), p.31155-31164
• Main Authors: Zhao, Xiaomin, Mohan, Ramkumar, Özcan, Sabire, Tang, Xiaoqing
• Format: Article
• Language: English
• Subjects: Animals; Cell Biology; Diabetes; Diabetes Mellitus - genetics; Diabetes Mellitus - metabolism; Diabetes Mellitus - pathology; Diabetes Mellitus - therapy; Down-Regulation - genetics; Exocytosis; Glucose; Humans; Insulin - biosynthesis; Insulin - genetics; Insulin Receptor Substrate Proteins - genetics; Insulin Receptor Substrate Proteins - metabolism; Insulin Secretion; Insulin Synthesis; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Maf Transcription Factors, Large - genetics; Maf Transcription Factors, Large - metabolism; MafA; Male; Mice; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; miR-30d; NF-kappaB-Inducing Kinase; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Transcription, Genetic - genetics; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.362632

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. Background: miR-30d induces insulin production, but the underlying mechanism remains unexplored. Results: miR-30d activates MafA by targeting TNF-α-activated MAP4K4. Conclusion: miR-30d promotes insulin production and protecting β-cell functions impaired by proinflammatory cytokines. Significance: Overexpression of miR-30d would be beneficial in preventing the development of diabetes.