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Regulation of Diminuto expression in endocrine cells and its function

Research Project

Project/Area Number 14571062
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Endocrinology
Research InstitutionNagoya University

Principal Investigator

KAMBE Fukushi  Nagoya Univ., Res.Inst.Environ.Med., Assoc.Prof., 環境医学研究所, 助教授 (00211871)

Co-Investigator(Kenkyū-buntansha) IMAI Tsuneo  Nagoya Univ., School of Med., Lecturer, 医学部, 講師 (80252245)
OHMORI Sachiko  Nagoya Univ., Res.Inst.Environ.Med., Res.Associate, 環境医学研究所, 助手 (20233273)
SEO Hisao  Nagoya Univ., Res.Inst.Environ.Med., Prof., 環境医学研究所, 教授 (40135380)
舟橋 啓臣  名古屋大学, 医学部, 講師 (50135357)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2003: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2002: ¥1,900,000 (Direct Cost: ¥1,900,000)
KeywordsDiminuto / DHCR24 / insulin / Akt / Bad / caveolin / ステロイド / ミトコンドリア
Research Abstract

We demonstrated that the human diminuto gene is overexpressed in benign cortisol-producing adrenocortical adenomas, and that its reduced expression is associated with increased apoptosis of adjacent normal cells. It was then reported that Diminuto catalyzes the last step of cholesterol biosynthesis, the conversion of desmosterol to cholesterol. To explore physiological function of Diminuto in mammalian cells, we investigated proliferation and apoptosis of mouse embryonic fibroblasts (MEF) prepared from diminuto-KO mice. Both KO-MEF and wild-type (WT)-MEF proliferated in the presence of 10% serum. However, serum withdrawal induced apoptosis of KO-MEF, but not WT-MEF. Interestingly, insulin rescued KO-MEF from the apoptosis, indicating that cholesterol depletion in KO-MEF by serum withdrawal might impair insulin-dependent cell survival signaling such as PI3K-Akt-Bad cascade. Indeed, phospho-Akt (S473) and Bad (S136) were more rapidly dephosphorylated in KO-MEF after serum withdrawal than those in WT-MEF. Furthermore, insulin-dependent phosphorylation of Akt and Bad in KO-MEF was much less in WT-MEF. The impaired insulin action was ascribed to cholesterol loss of plasma membrane, because treatment of WT-MEF with cyclodextrin, which selectively depletes cell surface of cholesterol, also impaired the insulin action. Since functional insulin receptor (IR) has been shown to be present in caveolae, the cholesterol-rich microdomain of plasma membrane, we isolated caveolae and examined IR and caveolin contents. It was demonstrated that IR and caveolin contents were reduced in KO-MEF. Taken together, these observations demonstrate that Diminuto plays an important role in insulin signaling and cell survival by controlling cholesterol biosynthesis and caveolae function.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] H.Mitsuyama, F.Kambe, et al.: "Calcium signaling Pathway involving calcineurin regulates interleukin-8 gene expression through activation of NF-kB in human osteoblast-like cells."Journal Bone and Mineral Research. (in press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] R.Murakami, F.kambe, et al.: "Cyclosporin A enhances interleukin-8 expression by inducing activator protein -1 in human aortic smooth muscle cells."Arteriosclerosis Thrumbosis and Vascular Biology. 23(11). 2034-2040 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] D.Zadworny, et al., F.Kambe, H.Seo: "The involvement of 3β-hydroxysterol-Δ^<24>-reducatase, a post-squalene enzyme in cholesterol biosynthesis, in desmosterolosis."Environmental Medicine. 47(1). 1-11 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] H.Kobayashi, T.Imai, F.Kambe, et al.: "Effect of ACTH on the proliferation of the rat adrenal gland."Environmental Medicine. 47(1). 20-21 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] X.Cao, F.Kambe, et al.: "Novel human ZAKI-4 isoforms : Hormonal and tissue-specific regulation and function as calcineurin inhibitors."Biochemical Journal. 367. 459-466 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] X.Cao, F.Kambe, et al.: "Oxidoreductive modification of two cysteine residues in paired domain by Ref-1 regulates DNA-binding activity of Pax-8."Biochumical and Biophysical Research Communications. 297. 288-293 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] MITSUYAMA Hirohito, KAMBE Fukushi, MURAKAMI Ryuichiro, CAG Xia, ISHIGURO Naoki, SEO Hisao: "Calcium signaling pathway involving calcineurin regulates interleukin-8 gene expression through activation of NF-κB in human osteoblast-like cells."Journal of Bone and Mineral Research. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] MURAKAMI Ryuichiro, KAMBE Fukushi, MITSUYAMA Hirohito, OKUMURA Kenji, MUROHARA Toyoaki, NIWATA Satoru, YAMAMOTO Ryohei, SEO Hisao: "Cyclosporin A enhances interleukin-8 expression by inducing activator protein-1 in human aortic smooth muscle cells."Arteriosclerosis Thrombosis and Vascular Biology. 23(11). 2034-2040 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] ZADWORNY David, SARKAR Devanand, IMAI Tsuneo, MIRZA Rusella, KAMBE Fukushi, SEO Hisao: "The involvement of 3β-hydroxysterol-Δ24-reductase, a post-squalene enzyme in cholesterol biosynthesis, in desmosterolosis."Environmental Medicine. 47(1). 1-11 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] KOBAYASHI Hironobu, IMAI Tsuneo, KAMBE Fukushi, MIRZA Rusella, SEO Hisao: "Effect of ACTH on the proliferation of the rat adrenal gland."Environmental Medicine. 47(1). 20-21 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] CAO Xia, KAMBE Fukudhi, MIYAZAKI Takashi, SARKAR Devanand, OHMORI Sachiko, SEO Hisao: "Novel human ZAKI-4 isoforms : Hormonal and tissue-specific regulation and function as calcineurin inhibitors."Biochemical Journal. 357. 459-466 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] GAO Xia, KAMBE Fukushi, OHMORI Sachiko, SEO Hisao: "Oxidoreductive modification of two cysteine residues in paired domain by Ref-1 regulates DNA-binding activity of Pax-8."Biochemical and Biophysical Research Communications. 297. 288-293 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] N.Mitsuyama, F.Kambe, et al.: "Calcium signaling pathway involving calcineurin regulates interleukin-8 gene expression through activation of NF-kB in human osteoblast-like cells"Journal Bone and Mineral Research. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] R.Murakami, F.kambe, et al.: "Cyclosporin A enhances interleukin-8 expression by inducing activator protein -1 in human aortic smooth muscle cells"Arteriosclerosis Thrombosis and Vascular Biology. 23(11). 2034-2040 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] D.Zadworny, F.Kambe, H.Seo, et al.: "The involvement of 3β-hydroxysterol-Δ^<24>-reducatase, a post-squalene enzyme in cholesterol biosynthesis, in desmosterolosis"Environmental Medicine. 47(1). 1-11 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] H.Kobayashi, T.Imai, F.Kambe, et al.: "Effect of ACTH on the proliferation of the rat adrenal gland"Environmental Medicine. 47(1). 20-21 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] X.Cao, F.Kambe, et al.: "Novel human ZAKI-4 isoforms : Hormonal and tissue-specific regulation and function as calcineurin inhibitors"Biochemical Journal. 367. 459-466 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] X.Cao, F.Kambe, et al.: "Oxidoreductive modification of two cysteine residues in paired domain by Ref-1 regulates DNA-binding activity of Pax-8"Biochemical and Biophysical Research Communications. 297. 288-293 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] X.Cao, F.Kambve, T.Miyazaki, S.Ohinori, H.Seo: "Novel human ZAKI-4 isoforms : Hormonal and tissue-specific regulation and function as calcineurin inhibitors"Biochemical Journal. 367. 459-466 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] X.Cao, Kambe, S.Ohmori, H.Seo: "Oxidoreductive modification of two cysteine residues in paired domain by Ref-1 regulates DNA-binding activity of Pax-8"Biochemical and Biophysical Research Communications. 297. 288-293 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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