| Project/Area Number |
10470485
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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 |
Biological pharmacy
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| Research Institution | Nagasaki University |
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Principal Investigator |
KOHNO Michiaki Nagasaki University, Pharmaceutical Sciences, Professor, 薬学部, 教授 (00027335)
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| Co-Investigator(Kenkyū-buntansha) |
HOSHINO Rika Nagasakil University, Pharmaceutical Sciences, Assistant Professor, 薬学部, 助手 (60315265)
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 2000: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 1999: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1998: ¥6,700,000 (Direct Cost: ¥6,700,000)
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| Keywords | Cell Proliferation / Cell Differentiation / Cell Motility / ERK-MAP kinase / p38 MAP kinase / p27^<Klp1> / Neurofilament Proteins / Matrix mettaloproteinase-9 / NF-M / MMP-9 / 核移行 / 肝細胞増殖因子 / 細胞分散運動 / 神経成長因子 / 神経細胞分化 / 細胞機能制御 / MAPキナーゼカスケード / ERK / TGF-βスーパーファミリー / 骨形成因子 |
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| Research Abstract |
(1) Blockade of the ERK-MAP kinase pathway by treatment with PD98059, a specific inhibitor of MEK, completely suppressed the growth of tumor cells in which the pathway is constitutively activated. Selective up-regulation of p27^<Klp1> was observed after PD98059 treatment of these tumor cells. The up-regulation of p27^<Klp1> correlated with increased association of p27^<Klp1> with cyclin E-CDK2 complexes, a concomitant inhibition of cyclin E-CDK2 kinase activity, and consequent decrease in the phosphorylation state of RB, which would culminate in the marked G1 cell cycle arrest observed in these tumor cells. These results suggest that the complete growth suppression that follows specific blockade of the ERK-MAP kinase pathway in tumor cells in which the pathway is constitutively activated is mediated by up-regulation of p27^<Klp1>.
(2) HGF induced the spreading, dissociation and scattering of MDCK cells. HGF induced the sustained activation of ERK-MAP kinases in the cells. We have examin
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ed whether or not the ERK-MAP kinase activity in the nucleus is required for HGF-induced scattering of MDCK cells. For the analysis, we forced cytoplasmic retention of ERK-MAP kinases in the cells by expressing an inactive form of the MKP-3 cytoplasmic phosphatase. The enforced cytoplasmic retention of the activated ERK-MAP kinases apparently inhibited the scattering response of MDCK cells in response to HGF.These results indicate that the ERK-MAP kinase activity in the nucleus is required for the motility response of MDCKcells induced by HGF.
(3) NGF has the capacity to induce the neuronal differentiation of PC12 cells. NGF induced the sustained activation of p38 MAP kinase pathway as well as of ERK-MAP kinase pathway. Pretreatment of PC12 cells with SB203580 (a specific inhibitor of p38 MAP kinase) or PD98059 partially inhibited the NGF-induced neurite outgrowth formation, while pretreatment of the cells with a combination of PD98059 and SB203580 resulted in almost complete inhibition of NGF-induced neurite outgrowth. These results suggest that activation of the ERK-MAP kinase pathway together with activation of p38 MAP kinase pathway are required for full induction of neurite outgrowth following stimulation of PC12 cells with NGF.ERK-MAP kinases are suggestively involved in the phosphorylation of neurofilament proteins (NFs), while p38 MAP kinase is involved in the expression of NF genes. Less
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