Identification of transacting factors responsible for the tissue-specific expression of human glucose transporter type 2 isoform gene - Cooperative role of hepatocyte nuclear factors 1 alpha and 3 beta

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We investigated transacting factors binding to the cis-element important in tissue-specific expression of the human glucose transporter type 2 isoform (GLUT2) gene. By transient transfection assay, we determined that the 227-base pair fragment upstream of the ATG start site contained promoter activity and that the region from +87 to +132 (site C) was responsible for tissue-specific expression. DNase I footprinting and electrophoretic mobility shift assay indicated that site C contained one binding site for hepatocyte nuclear factor 1 (HNF1) and two binding sites for HNF3 The mutations at positions +101 and +103, which are considered to be critical in binding HNF1 and HNF3, resulted in a 53% decrease in promoter activity, whereas the mutation of the proximal HNF3 binding site (+115 and +117) reduced promoter activity by 28%. The mutations of these four sites resulted in marked decrease (70%) in promoter activity as well as diminished bindings of HNF1 and HNF3, A to G mutation, which causes conversion of the HNF1 and HNF3 binding sequence to the NF-Y binding site, resulted in a 22% decrease in promoter activity. We identified that both HNF1 and HNF3 function as transcriptional activators in GLUTS gene expression. Coexpression of the pGL+74 (+74 to +301) construct with the HNF1 alpha and HNF3 beta expression vectors in NIH 3T3 cells showed the synergistic effect on GLUTS promoter activity compared with the expression of HNF1 alpha, HNF3 beta, or a combination of HNF1 beta and HNF3 beta. These data suggest that HNF1 alpha and HNF3 beta may be the most important players in the tissue-specific expression of the human GLUTS gene.
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Issue Date
2000-06
Language
English
Article Type
Article
Keywords

LIVER-SPECIFIC TRANSCRIPTION; PANCREATIC BETA-CELL; TRANS-ACTING FACTORS; GLUT2 EXPRESSION; INSULIN GENE; PROMOTER; BINDING; ACTIVATION; METABOLISM; ENHANCER

Citation

JOURNAL OF BIOLOGICAL CHEMISTRY, v.275, no.24, pp.18358 - 18365

ISSN
0021-9258
DOI
10.1074/jbc.M909536199
URI
http://hdl.handle.net/10203/77801
Appears in Collection
MSE-Journal Papers(저널논문)
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