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Biochem Biophys Res Commun. 2005 Apr 15;329(3):984-90.

Functional characterization of the HNF4alpha isoform (HNF4alpha8) expressed in pancreatic beta-cells.

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  • 1Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan.

Abstract

Mutations in the hepatocyte nuclear factor (HNF) 4alpha gene cause a form of maturity-onset diabetes of the young (MODY1), which is a monogenic form of type 2 diabetes characterized by impaired insulin secretion by pancreatic beta-cells. HNF4alpha is a transcription factor expressed in the liver, kidney, intestine, and pancreatic islet. Multiple splice variants of the HNF4alpha gene have been identified and an isoform of HNF4alpha8, an N-terminal splice variant, is expressed in pancreatic beta-cells. However, expression levels of HNF4alpha protein in pancreatic beta-cells and the transcriptional activity of HNF4alpha8 are not yet understood. In the present study, we investigated the expression of HNF4alpha in beta-cells and examined its functional properties. Western blotting and immunohistochemical analysis revealed that the expression of HNF4alpha protein in pancreatic islets and INS-1 cells was much lower than in the liver. A reporter gene assay showed that the transactivation potential of HNF4alpha8 was significantly weaker than that of HNF4alpha2, which is a major isoform in the liver, suggesting that the total level of HNF4alpha activity is very weak in pancreatic beta-cells. We also showed that the N-terminal A/B region of HNF4alpha8 possessed no activation function and C-terminal F region negatively regulated the transcriptional activity of HNF4alpha8. The information presented here would be helpful for the better understanding of MODY1/HNF4alpha diabetes.

PMID:
15752752
[PubMed - indexed for MEDLINE]
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