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Signal transduction mechanism of cell death-role of kinase cascade.

Research Project

Project/Area Number 07670706
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionFukui Medical School

Principal Investigator

MUTOH Tatsuro  Fukui Medical School, Lectureer, 医学部附属病院, 講師 (60190857)

Co-Investigator(Kenkyū-buntansha) HAMAGUCHI Michinari  Nagoya University, Professor, 医学部, 教授 (90135351)
KURIYAMA Masaru  Fukui Medical School, Professor, 医学部, 教授 (80107870)
Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1996: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1995: ¥1,800,000 (Direct Cost: ¥1,800,000)
Keywordsapoptosis / HMG-CoA reductase / inhibitor / Tyrosine phospholation / PLC-gamma1 / L6 muoblasts / イソプレニレーション / チロシンキナーゼ
Research Abstract

To understand molecular mechanism of many neurodegenerative disorders, we should elucidate how neurons and muscle cells die and the signals for cell death in such diseases. Accumulating evidences have suggested that apoptotic cell death can occur in patients' brain from some neurodegenerative disorders. We have been involved in the study of the intracellular signal transduction pathway of apoptotic cell death in terms of intracellular protein kinase casccade. In this project, we tried to develope the model system where cells die through apoptotic mechanism in neuronal culture systems and examine the intracellular signal transduction pathway of apoptotic cell death. For these purposes, we found that L6 myocytes are killed by HMG-CoA reductase inhibitor (HCRI), widely used medicine for the treatment of hypercholesteroraemia, involving the induction of apoptotic mechanism. Hydrophobic derivative of HCRIs, simvastatin kills L myocytes at the concentration of 30 ug/ml and causes internucleo … More somal DNA fragmentation and tyrosine phosphorylation reaction of several cellular proteins. Herbimycin A or genistein, a potent inhibitor of protein tyrosine kinase activity prevented simvastatin-induced apoptotic cell death. In the next step, we tried to identify the protein which got tyrosine phosphorylated in response to simvastatin treatment and succeeded in identifying one of such proteins. Phospholipase C-gamma 1 was found to be tyrosine-phosphorylated in simvastatin-treated cells. Tyrosien phosphorylation of PLC-gamma1 was evident as early as 2 min after addition of simvastatin into culture medium and reached maximum at 10 min after its addition. Heretofore, PLC-gamma1 is activated when it gets tyrosine-phosphorylated, although tyrosine phosphorylation is not the only way for the activation. Therefore, we tried to check whether simvastatin induces PI turnove in simvastatin treated cells. Intracellular concentration of IP3 increased up to 3-fold than the basal level at 10 min after addition of simvastatin. U73122, a potent inhibitor of PLC,clear inhibited simvastatin-induced cell death. These results indicate the special role of tyrosine phosphoryaltion and PLC activity in apoptotic cell death of muscle cells. Less

Report

(3 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] TMutoh et al: "Ganglioside GMlibinds to the TrK protein and regulates receptor function" Proc Natl Acad Sci USA. 92. 5087-5091 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] 武藤 多津郎 他: "リソソーム病-マススクリーニング法" 日本臨床. 53. 2933-2937 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] M Pu et al: "Evidence of novel redox-linked activation mechanism for the Src kinase which is independent of tyrosine 527-mediated regulation" Oncogene. 13. 2615-2622 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] M Pu et al: "Mercuric chloride mediates a protein sulfhydryl modification based pathway of signal transduction for activating Src kinase" J Cell Biochem. 63. 104-114 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] M Hirayama: "Chorea-acanthocytosis with polyelonal antibodies to ganglioside GMl" J Neurol Sci. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] T Mutoh, A Tokuda, T Miyadai, M Hamaguchi, N Fujiki: "Ganglioside GM1 binds to the Trk protein and regulates receptor function" Proc Natl Acad Sci USA. 92. 5087-5091 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] M Pu et al.: "Evidence of novel redox-linked activation mechanism for the Src kinase which is independent of tyrosine 527-mediated regulation" Oncogene. 13. 2615-2622 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] T Mutoh, M Kuriyama: "Lysosomal storage dieases.--Methods for mass screening" Jap Clin. 53. 2933-2937 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] M Hirayama et al.: "Chorea-acanthocytosis with polyclonal antibodies to ganglioside GM1" J Neurol Sci. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Pu M.et al.: "Evidence of a novel redox-linked activation mechanisin for the Sro Kinase which is independent of tyrosine 527-mediated regulation" Oncogene. 13. 2615-2622 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Pu M.et al.: "Mecuric chloride mediates a protein sulfhydryl modification-based pathway of signal transduction for activating Src Kinase which is independent" J Cell Biochem. 63. 104-114 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hirayama M.et al.: "Chorea-acanthocytosis with polyolonal antibodies to ganglioside GMI" J Neurol Sci. (in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] T.Mutoh et al: "Ganglioside GHi binds to the TrK protein and regulates receptor function" Proc.Natl Acad Sci,USA. 92. 5087-5091 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 武藤多津郎,栗山勝: "リソゾーム病-マススクリーニング法" 日本臨床. 53. (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 武藤多津郎,栗山勝: "リソゾーム病-マススクリーニング法" 日本臨床. 53. (1995)53-57

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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