| Project/Area Number |
03454155
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
General medical chemistry
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| Research Institution | The University of Tokyo |
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Principal Investigator |
SUZUKI Koichi Univ. of Tokyo, Inst. Appl. Micro., Prof., 応用微生物研究所, 教授 (80011948)
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| Co-Investigator(Kenkyū-buntansha) |
AKITA Yoshiko Tokyo, Metropol. Inst. Med. Sci. Research, 遺伝情報, 研究員 (40124432)
TOMIOKA Shigeo Univ. of Tokyo, Inst. Appl. Microbiol., Assistant, 応用微生物研究所, 教務職員 (90159046)
SAIDO Takaomi Tokyo, Metropol. Inst. Med. Sci. Research, 遺伝情報, 研究員 (80205690)
ISHIURA Shoichi Univ. of Tokyo, Inst. Appl. Micro., Assoc. Prof, 応用微生物研究所, 助教授 (10158743)
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| Project Period (FY) |
1991 – 1992
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| Project Status |
Completed (Fiscal Year 1992)
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| Budget Amount *help |
¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 1992: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1991: ¥4,300,000 (Direct Cost: ¥4,300,000)
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| Keywords | Protein Kinase C / calpain / calcium / signal transduction / プロテインキナ-ゼC / ダウンレギュレ-ション / ホルボ-ルエステル |
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| Research Abstract |
To clarify the mechanism of down-regulation of protein kianse C, and its implication in cellular signal transduction, studies on calpain and protein kinase C (PKC) were performed. Calpain and PKC translocate simultaneously to the biological membrane upon binding calcium ions when the cell surface receptor is activated by ligands and intracellular calcium concentrations increase. PKC is activated at the membrane in the presence of calcium by diacylglycerol and phospholipids. Calpain is also activated at the membrane autocatalytically in the presence of calcium and phosphatidylinositol-4,5- bisphosphate. Activated calpain acts on activated PKC and hydrolyzes bonds between the N-terminal regulatory domain and the C-terminal kinase domain to give an active fragment of PKC which is active without cofactors. Calpain recongnizes only the active and phosphorylated species and inactive PKC is not hydrolyzed. The role of the active fragment is not clear yet. It may be an intermediate of degradation or have some physiological function in transduction of signal from the membrane to the nucleus.
Calpain hydrolyzes transcription factors, such as c-Jun and c-Fos, leading to down-regulation of cellular signals induced by activation of receptors. Activation of calpain stops the cellular signal transduction pathway at least by hydrolyzing PKC and transcription factors.
Activated calpain is very unstable and presumably used only once. The calpain gene is a phorbol ester responsive gene and its transcription is induced by treatment of cells by various stimuli, such as growth factors, phorbol ester, etc. Newly synthesized calpain refills the calpain pool used to down-regulate signal transduction.
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