| Project/Area Number |
11557185
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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 | 展開研究 |
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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, School of Pharmaceutical Sciences, Professor, 薬学部, 教授 (00027335)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUMURA Yoshihiro Nagasaki University, School of Pharmaceutical Sciences, Professor, 薬学部, 教授 (60026309)
KOUNO Isao Nagasaki University, School of Pharmaceutical Sciences, Professor, 薬学部, 教授 (20038607)
OZAKI Ken-ichi Nagasaki University, School of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (50252466)
星野 理香 長崎大学, 薬学部, 助手 (60315265)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥13,600,000 (Direct Cost: ¥13,600,000)
Fiscal Year 2001: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1999: ¥6,500,000 (Direct Cost: ¥6,500,000)
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| Keywords | MAP kinase pathway / ERK-MAP kinase / c-Jun N-terminal kinase / Specific inhibitor / Anti-tumor agent / Anti-inflammatory agent / Molecular Target / Polyphenol / 特異的阻害剤 / p38MAPキナーゼ / フラボン / MAPキナーゼ / MAPキナーゼキナーゼ / シグナル分子 |
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| Research Abstract |
(1) Blockade of the ERK-MAP kinase pathway bytreatment 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 alter PD98059 treatment of these tumorcells. 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. Furthermore, PD98059-treatment induced a modest apoptotic response in several tumor cells in which the ERK-MAP pathway is constitutively activated. In cotrast, although PD98059 inhibited the proliferation of human diploid fibroblasts to a considerable degree, it never caused any apoptotic response in these cells. Moreover, growth-inhibited diploid fibroblasts reinitiated proliferation
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soon after removal of the inhibitor. These results strongly suggest that the the ERK-MAP kinase pathway is a potential therapeutic target in a group of tumor cells in which the pathway is constitutively activated.
(2) Several polyphenols isolated from green tea leaves potently inhibited the ERK-MAP kinase pathway. These were (-)-epigallocatechin-3-gallate (EGCG) and its derivates. The molecular target of these polyphenols was suggested not to be MEK. Furthermore, several thiofravone derivativates of PD98059 such as 2-(2-amino-3-methoxyphenyl) thiochromone and 2-(2-amino-3-chrophenyl) thiochromone inhibited MEk activity more strongly than PD98059 in in vitro and in vivo experiments.
(3) An anthrapyrazolone derivative (SP600125), which was originally developed as a potent inhibitor against c-Jun N-terminal kinase, was synthesized. This compound inhibited the growth of many tumor cells by arresting them at G2/M phase but not at G1 phase of the cell cycle. Thus, this compound issuggested to provide us with anew type of anti-tumor agent. Less
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