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© 2002 by the American Diabetes Association, Inc.
Hepatocyte Nuclear Factor-1
Recruits the Transcriptional Co-Activator p300 on the GLUT2 Gene Promoter
1 Department of Metabolism and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Japan
2 Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Japan
3 Graduate School of Human and Environmental Studies, Kyoto University, Japan
Mutations in the hepatocyte nuclear factor (HNF)-1
gene have been linked to subtype 3 of maturity-onset diabetes of the young (MODY), a disease characterized by a primary defect in insulin secretion. Here we show that the human GLUT2 gene is closely regulated by HNF-1 via sequences downstream of the transcriptional start site by interaction with transcriptional co-activator p300. The promoter region of the human GLUT2 gene was subcloned into luciferase expression plasmids that were transfected together with HNF-1 expression plasmid into a pancreatic ß-cell line, HIT-T15, to evaluate transcriptional activities. HNF-1 enhanced human GLUT2 promoter activity sixfold. Site-direct mutagenesis and footprint analyses showed that the HNF-1 binding site (+200 to +218) is critical in human GLUT2 gene expression. Furthermore, mammalian two-hybrid and immunoprecipitation studies revealed the transactivation domain of HNF-1 (amino acids 391–540) to interact with both the NH2-terminal region (amino acids 180–662) and the COOH-terminal region (amino acids 1,818–2,079) of p300. These findings demonstrated that HNF-1 binds to the 5'-untranslated region of GLUT2 and that p300 acts as a transcriptional co-activator for HNF-1. In addition, these results provided new insight into the regulatory function of HNF-1 by suggesting a molecular basis for human GLUT2 gene expression.
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