2001 Fiscal Year Final Research Report Summary
Development of specific inhibitors against MAP kinase pathways
| 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)
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| Project Period (FY) |
1999 – 2001
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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 |
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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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[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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[Publications] Hattori, A., Katayama, M., Iwasaki, S., Ishii, K., Tsujimoto, M. & Kohno, M.: "Bone morphogenetic protein-2 promotes survival and differentiation of striatal GAB Aergic neurons in vitro in the absence of glial cell proliferation"J. Neurochem. 72. 2264-2271 (1999)
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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., Nuruzaman, 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., Kadomoto, R., Asato, K., Tanimujra, S., Itoh, N. & Kohno, M.: "Extracellular signal-regulated kinase pathway positively regulates the expression of Sprouty genes"Biochem. Biophys. Res. Commun.. 285. 1084-1088 (2001)
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