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Determine the molecular mechanism of insulin gene expression for the regeneration of pancreatic islets

Research Project

Project/Area Number 15590944
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionKagawa University

Principal Investigator

ISHIDA Toshihiko  Kagawa University, faculty of Medicine, First Department of Internal Medicine, Professor, 医学部, 教授 (50159737)

Co-Investigator(Kenkyū-buntansha) MURAO Koji  Kagawa University, Faculty of Medicine, Assistant Professor, 医学部附属病院, 助手 (20291982)
TOKUMITSU Hiroshi  Kagawa University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (20237077)
YOSHITAKA Sayo  Kagawa University, Faculty of Medicine, Assistant Professor, 医学部附属病院, 助手 (20343311)
OHNISHI Hiroaki  Kagawa University, Faculty of Medicine, Assistant Professor, 医学部, 助手 (90223891)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
Keywordsinsulin / Diabetes Mellitus / glucose / CaMKK / CaMKIV / PREB / IB1 / IB-1
Research Abstract

A number of factors have been reported to affect insulin synthesis in beta-cells. Although glucose is the most important regulator of insulin gene expression in pancreatic beta-cells, the mechanisms whereby glucose stimulates insulin gene transcription in response to changes in glucose concentration have not been clarified yet. In this study, we examined the role of the Ca(2+)/calmodulin (CaM)-dependent protein kinase (CaM-K) cascade in transcriptional activation of insulin. RT-PCR, Western blotting, and immunohistochemical staining analysis revealed that CaM-K kinase-alpha (CaM-KKalpha) and CaM-KIV were localized in rat pancreatic beta-cells and their cell line, INS-1. Exposure of INS-1 cells to 11.2 mmol/l glucose elicited an increase of insulin promoter activity as well as upregulation of CaM-KIV activity within 2 min after stimulation. We investigated the influence on insulin promoter activity of the constitutively active form (CaM-KIVc) or dominant-negative mutant (CaM-KIVdn) of CaM-KIV in transfected INS-1 cells. CaM-KIVc alone was sufficient, and the upstream kinase, CaM-KK, was enhanced to upregulate the insulin promoter activity in INS-1 cells. Furthermore, cotransfection of CaM-KIVdn suppressed to a significant degree the glucose-upregulated activity of the insulin promoter. Taken together, these results indicated that the CaM-KK/CaM-KIV cascade might play an important role in glucose-upregulated transcriptional activation of the insulin gene. We have also determined the role of PREB and IB 1 as a transcriptional factor for insulin gene transcription.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (19 results)

All 2004 2003 Other

All Journal Article (15 results) Publications (4 results)

  • [Journal Article] Insulin like growth factor-I Regulation of hepatic scavenger receptor class BI2004

    • Author(s)
      Cao WM, et al.
    • Journal Title

      ENDOCRINOLOGY 145

      Pages: 5540-5547

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Lipid-Altering Drugs : Decreasing Cardiovascular Disease at the Expense of Increasing Cancer?2004

    • Author(s)
      Murao K, et al.
    • Journal Title

      Cancer Research 64

      Pages: 6831-6832

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] A Mutant HDL Receptor Inhibits Proliferation of Human Breast Cancer Cells.2004

    • Author(s)
      Cao WM, et al.
    • Journal Title

      Cancer Research 64

      Pages: 1515-1521

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Phosphatidylserine Receptor in Apoptotic Function of Nursing Thymic Epithelial Cells2004

    • Author(s)
      Cao WM, et al.
    • Journal Title

      J Mol Endocrinol 32

      Pages: 497-505

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] The role of calcium/calmodulin-dependent protein kinase cascade in glucose upregulation of insulin gene expression.2004

    • Author(s)
      Yu X, et al.
    • Journal Title

      Diabetes 53

      Pages: 1475-1481

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Role of calcium-calmodulin dependent protein kinase cascade in TRH upregulation of TSH and PRL gene expression.2004

    • Author(s)
      Murao K, et al.
    • Journal Title

      ENDOCRINOLOGY 145

      Pages: 4846-4852

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] TRH-stimulated TSH expression involves Islet-Brain-1/c-Jun N-terminal Kinase Interacting protein-1.2004

    • Author(s)
      Abe H, Murao K, Imachi H, Cao WM, Yu X, Yoshida K, Wong NCW, Shupnik MA, Haefliger JA, Waeber G, Ishida T.
    • Journal Title

      Endocrinology 145

      Pages: 5623-5628

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Insulin like growth factor-I Regulation of hepatic scavenger receptor class BI2004

    • Author(s)
      Cao WM, Murao K, Imachi H, Yu X, Dobashi H, Yoshida K, Muraoka T, Kotsuna N, Nagao S, Wong NCW, Ishida T.
    • Journal Title

      Endocrinology 145

      Pages: 5540-5547

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Role of calcium-calmodulin dependent protein kinase cascade in TRH upregulation of TSH and PRL gene expression.2004

    • Author(s)
      Murao K, Imachi H, Yu X, Cao WM, Tokumitsu H, Inuzuka H, Wong NCW, Shupnik MA, Kobayashi R, Ishida T.
    • Journal Title

      Endocrinology 145

      Pages: 4846-4852

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Lipid-Altering Drugs : Decreasing Cardiovascular Disease at the Expense of Increasing Cancer?2004

    • Author(s)
      Murao K, Imachi H, Wong NC, Ishida T
    • Journal Title

      Cancer Res. 64

      Pages: 6831-6832

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The role of calcium/calmodulin-dependent protein kinase cascade in glucose upregulation of insulin gene expression.2004

    • Author(s)
      Yu X, Murao K, Sayo Y, Imachi H, Cao WM, Ohtsuka S, Niimi M, Tokumitsu H, Inuzuka H, Wong NC, Kobayashi R, Ishida T.
    • Journal Title

      Diabetes. 53

      Pages: 1475-1481

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A Mutant HDL Receptor Inhibits Proliferation of Human Breast Cancer Cells.2004

    • Author(s)
      Cao WM, Murao K, Imachi H, Yu X, Abe H, Yamauchi A, Niimi M, Miyauchi A, WongNCW, Ishida T.
    • Journal Title

      Cancer Res 64

      Pages: 1515-1521

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phosphatidylserine Receptor in Apoptotic Function of Nursing Thymic Epithelial Cells2004

    • Author(s)
      Cao WM, Murao K, Imachi H, Hiramine C, Yu X, Abe H, Wong NCW, Ishida T
    • Journal Title

      J Mol Endocrinol. 32

      Pages: 497-505

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Design and Baseline Characteristics of a Study of Primary Prevention of Coronary Events With Pravastatin Among Japanese With Mildly Elevated Cholesterol Levels2004

    • Author(s)
      MEGA Study Group
    • Journal Title

      Circulation Journal 68

      Pages: 860-867

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression of human scavenger receptor B1 on and in human platelets2003

    • Author(s)
      Imachi H, Murao K, Cao WM, Tada S, Taminato T, WongNCW, Takahara J, Ishida T
    • Journal Title

      Arterioscler Thromb Vase Biol 23

      Pages: 898-904

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Imachi H, Murao K. et al.: "Expression of human scavenger receptor B1 on and in human platelets."Arterioscler Thromb Vasc Biol.. 23. 898-904 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Cao WM, Murao K et al.: "A mutant high-density lipoprotein receptor inhibits proliferation of human breast cancer cells."Cancer Res. 64. 1515-1521 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Cao WM, Murao K et al.: "Phosphatidylserine Receptor Cooperates with High Density Lipoprotein Receptor on Recognition of Apoptotic Cells by Thymic Nurse Cells."J Mol Endocrinol. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Yu X, Murao K et al.: "Role of calcium-calmodulin dependent protein kinase cascade in glucose upregulation of insulin gene expression."Diabetes. (in press).

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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