2002 Fiscal Year Final Research Report Summary
Analysis of transcriptional network in pancreatic β-cells
| Project/Area Number |
12470228
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
SEINO Yutaka Kyoto University Graduate School of Medicine Professor, 医学研究科, 教授 (40030986)
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| Co-Investigator(Kenkyū-buntansha) |
YAMADA Yuichiro Kyoto University Graduate School of Medicine Associate Professor, 医学研究科, 助教授 (60283610)
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| Project Period (FY) |
2000 – 2002
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| Keywords | pancreatic β-cell line / Tet expression system / SAGE / Transcription factor / Target gene / GLUT2 / Proliferation and differentiation |
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| Research Abstract |
Mutations in the hepatocyte nuclear factor (HNF)-1α 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-1α via sequences downstream of the transcriptional start site by interaction with transcriptional coactivator p300. The promoter region of the human GLUT2 gene was subcloned into luciferase expression plasmids that were transfected together with HNF-1α expression plasmid into a pancreatic β-cell line, HIT-T15, to evaluate transcriptional activities. HNF-1α enhanced human GLUT2 promoter activity sixfold. Site-direct mutagenesis and footprint analyses showed that the HNF-1α 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-1α (amino acids 391-540) to interact with both the NH_2-terminal region (amino acids 180-662) and the COOH-terminal region (amino acids 1,818-2,079) of p300. These findings demonstrated that HNF-1α binds to the 5'-untranslated region of GLUT2 and that p300 acts as a transcriptional coactivator for HNF-1α. In addition, these results provided new insight into the regulatory function of HNF-1α or by suggesting a molecular basis for human GLUT2 gene expression.
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[Publications] Pamir N, Lynn FC, Buchan AM, Ehses J, Hinke SA, Pospisilik JA, Miyawaki K, Yamada Y, Seino Y, McIntosh CH, Pederson RA: "Glucose-dependem Insulinotropic Polypeptide Receptor Null Mice (GIPR-/-) Exhibit Compensatory Changes in the Enteroinsular Axis"Am J Physiol. 284. E931-E939 (2003)
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「研究成果報告書概要(欧文)」より
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[Publications] Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K, Zhou H, Fujimoto S, Oki A, Tsuda K, Toyokuni S, Hiai H, Mizunoya W, Fushiki T, Holst JJ, Makino M, Tashita A, Kobara Y, Tsubamoto Y, Jinnouchi T, Jomori T, Seino Y: "Inhibition of gastric inhibitory polypeptide signaling prevents obesity"Nat Med. 8(7). 738-742 (2002)
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[Publications] Kuroe A, Fukushima M, Usami M, Ikeda M, Nakai Y, Taniguchi A, Matsuura T, Suzuki H, Kurose T, Yasuda K, Yamada Y, Seino Y.: "Impaired β-cell function and insulin sensitivity in Japanese subjects with normal glucose tolerance"Diabetes Res Clin Pract. 59(1). 71-77 (2002)
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「研究成果報告書概要(欧文)」より
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[Publications] Taniguchi A, Nagasaka S, Fukushima M, Sakai M, Okunmra T, Yoshii S, Watanabe T, Ogura M, Yamadori N, Nin K, Kuroe A, Yamada Y, Seino Y, Nakai Y: "C-reactive protein and insulin resistance in non-obese Japanese type 2 diabetic patients"Metabolism. 51(12). 1578-1581 (2002)
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「研究成果報告書概要(欧文)」より
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[Publications] Takeda T, Tsuura Y, Fujita J, Fujimoto S, Mukai E, Kajikawa M, Hamamoto Y, Kume M, Yamamoto Y, Yamaoka Y, Yamada Y, Seino Y: "Heat shock restores insulin secretion after injury by nitric oxide by maintaining glucokinase activity in rat islets"Biochem Biophys Res Commun. 284(1). 20-25 (2001)
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[Publications] Ban N Yamada Y, Someya Y, Ihara Y, Adachi T, Kubota A, Watanabe R, Kuroe A, Inada A, Miyawaki K, Sunaga Y, Shen ZP, Iwakura T, Tsukiyama K, Toyokuni S, Tsuda K, Seino Y: "Activating transcription factor-2 is a positive regulator in CaM kinase IV-induced human insulin gene expression"Diabetes. 49(7). 1142-1148 (2000)
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「研究成果報告書概要(欧文)」より
