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ABSTRACT: Elucidating the mechanism underlying the poor proliferative capacity of adult pancreatic β cells is critical to regenerative therapeutic approaches for diabetes. Here, we show that the miR-7/7ab family member microRNA-7a (miR-7a) is enriched in mouse adult pancreatic islets compared with miR-7b. Remarkably, miR-7a targets five components of the mTOR signaling pathway. Further, inhibition of miR-7a activates mTOR signaling and promotes adult β-cell replication in mouse primary islets, which can be reversed by the treatment with a well-known mTOR inhibitor, rapamycin. These data suggest that miR-7 acts as a brake on adult β-cell proliferation. Most importantly, this miR-7-mTOR proliferation axis is conserved in primary human β cells, implicating miR-7 as a therapeutic target for diabetes.
Diabetes 12/2012; · 8.29 Impact Factor
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ABSTRACT: Hyperglycemia increases insulin flux through the endoplasmic reticulum (ER) of pancreatic β-cells, and the unfolded protein response pathway is required to enhance insulin processing. Pancreatic and duodenal homeobox 1 (PDX1), a key pancreatic transcription factor, regulates insulin along with targets involved in insulin processing and secretion. Here we find that PDX1 is a direct transcriptional regulator of ER oxidoreductin-1-like β (Ero1lβ), which maintains the oxidative environment of the ER to facilitate disulfide bond formation. PDX1 deficiency reduced Ero1lβ transcript levels in mouse islets and mouse insulinoma (MIN6) cells; moreover, PDX1 occupied the Ero1lβ promoter in β-cells. ERO1lβ levels were induced by high glucose concentrations and by the reducing agent dithiothreitol, indicating potential roles in adaptation to increased oxidative protein folding load in the β-cell ER. In MIN6 cells, small interfering RNA-mediated silencing of Ero1lβ decreased insulin content and increased susceptibility to ER stress-induced apoptosis. These findings demonstrate roles for the PDX1 target ERO1lβ in maintaining insulin content and regulating cell survival during ER stress.
Endocrinology 07/2011; 152(7):2599-608. · 4.46 Impact Factor
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ABSTRACT: Three-amino-acid-loop-extension (TALE) homeodomain proteins including Meis and Pbx families are generally recognized for their roles in growth and differentiation during vertebrate embryogenesis and tumorigenesis. Whereas genetic studies indicate that Pbx1 regulates the development and function of insulin-producing pancreatic β-cells, the role of Meis family members in β-cells is still unknown. Here we show that Meis3 is abundantly expressed in pancreatic islets and β-cells and that it regulates β-cell survival. We further identify the 3-phosphoinositide-dependent protein kinase 1 (PDK1), a well-known kinase involved in the PI3K-Akt signaling pathway, as a direct Meis3 target, which mediates its role in β-cell survival. This regulatory module appears to function broadly as we also identify Meis3 regulation of cell survival and PDK1 expression in ovarian carcinoma cells, suggesting a unique function for Meis3 beyond the traditional roles for TALE homeodomain factors during embryogenesis.
Proceedings of the National Academy of Sciences 11/2010; 107(47):20494-9. · 9.68 Impact Factor
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ABSTRACT: 1A6/DRIM is a nucleolar protein with a nucleolar targeting sequence in its 3'-terminus. Bioinformatic analysis indicated that human 1A6/DRIM shares 23% identity and 43% similarity with yeast Utp20, which has been reported as a component of U3 snoRNA protein complex and has been implicated in 18S rRNA processing. In the present study, we found, by utilizing RT-PCR with RNA extracted from anti-1A6/DRIM immunoprecipitates and Northern blotting, that 1A6/DRIM is associated with U3 snoRNA. Pulse-chase labeling assays showed that silencing of 1A6/DRIM expression in HeLa cells resulted in a delayed 18S rRNA processing. Furthermore, immunoprecipitations revealed that 1A6/DRIM was also associated with fibrillarin, another U3 RNP component in HeLa cells. These results indicate that 1A6/DRIM is involved in 18S rRNA processing and is the bona fide mammalian Utp20.
Biochimica et Biophysica Acta 07/2007; 1773(6):863-8. · 4.66 Impact Factor
