2000 Fiscal Year Final Research Report Summary
Role of MAP Kinase Cascade in the Regulation of Diverse Cellular Fuctions.
| 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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| Keywords | Cell Proliferation / Cell Differentiation / Cell Motility / ERK-MAP kinase / p38 MAP kinase / p27^<Klp1> / Neurofilament Proteins / Matrix mettaloproteinase-9 |
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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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[Publications] Tanimura, S., Chatani, Y., Hoshino, R., Sato, M., Watanabe, S., Kataoka, T., Nakamura, T.& Kohno, M.: "Activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway is required for hepatocyte growth factor-induced cell scattering."ONCOGENE. 17. 57-65 (1998)
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[Publications] Hashimoto, H., Yokoyama, Y., Matsuo, Y., Toyohara, H., Kohno, M.& Sakaguchi, M.: "Existence of two isoforms of extracellular-signal regulated kinase infish."J.Biochem.. 123. 1031-1035 (1998)
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[Publications] Hoshino, R., Chatani, Y., Yamori, T., Tsuruo, T., Oka.H., Yoshida, O., Shimada, Y., Ari-i, S., Wada, H., Fujimoto, J.& Kohno, M.: "Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors."ONCOGENE.. 18. 813-822 (1999)
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「研究成果報告書概要(欧文)」より
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[Publications] Hattori, A., Katayama, M., Iwasaki, S., Ishii, K., Tsujimoto, M.& Kohno, M.: "Bone morphogenetic protein-2 promotes survival and differentiation of striatal GABAergic neurons in vitro in the absence of glial cell proliferation."J.Neurochem.. 72. 2264-2271 (1999)
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「研究成果報告書概要(欧文)」より
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[Publications] Iwasaki, S., Iguchi, M., Watanabe, K., Hoshino, R., Tsujimoto, M.& Kohno, M.: "Specific activation of the p38 Mitogen-activated protein kinase signaling pathway and induction of neurite outgrowth in PC12 cells by bone morphogenetic protein-2."J.Biol.Chem.. 274. 26503-26510 (1999)
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[Publications] Fuji, K., Watanabe, Y., Ohtsubo, T., Nuruzzaman, M., Hamajima, Y.& Kohno, M.: "Synthesis of extremely simplified compounds possessing the key pharmacophore units of taxol, phenylisoserine and oxetane moieties."Chem.Pharm.Bull.. 47. 1334-1337 (1999)
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[Publications] Ozaki, K., Kadomoio, R., Asato, K., Tanimura, S., Itoh, N.& Kohno, M.: "Extracellular signal-regulated kinase pathway positively regulates the expression of Sprouty genes."Biochme.Biophys.Res.Commun.. (in press). (2001)
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