Role of MAP kinase cascades in the regulation of diverse cellular functions
| Project/Area Number |
17390020
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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, Graduate School of Biomedical Sciences, Professor, 大学院医歯薬学総合研究科, 教授 (00027335)
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| Co-Investigator(Kenkyū-buntansha) |
OZAKI Kei-ichi Nagasaki University, Graduate School of Biomedical Sciences, Associate Professor, 大学院医歯薬学総合研究科, 助教授 (50252466)
TANIMURA Susumu Nagasaki University, Graduate School of Biomedical Sciences, Assistant Professor, 大学院医歯薬学総合研究科, 助手 (90343342)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2006: ¥6,100,000 (Direct Cost: ¥6,100,000)
Fiscal Year 2005: ¥8,900,000 (Direct Cost: ¥8,900,000)
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| Keywords | ERK-MAP Kinase / Intracellular Localization / GEF-H1 / Cell Motility / c-Jun N-terminal Kinase / Intermediate Filaments / Cell Cycle / Spindle Checkpoint / スピンドルチェックポイント / p90^<RSK> / RhoA / 細胞内局在性 / ケラチン8 / 細胞質分裂 |
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| Research Abstract |
1. We have examined a possible molecular mechanism through which nuclear translocation and retention of ERK-MAP kinases is regulated. A novel 26-kD protein (p26) which contains a SH3 domain at the N-terminus and three ankyrin repeat sequences at the C-terminus has been identified as a candidate molecule which is involved in the regulation of nuclear translocation/retention of ERK-MAP kinases. Overexpression of p26 suppresses the HGF-induced nuclear localization/retention of ERK-MAP kinases in MDCK cells, while siRNA-mediated knockdown of p26 enhances it. p26 interact specifically with a novel 120-kDa protein (p120), and this interaction is suppressed by the phosphorylation of p26 by p90^<rsk>, an effector molecule downstream of the ERK-MAP kinases. These results suggest that nuclear translocation/retention of ERK-MAP kinases is regulated by the ERK-MAP kinase signaling pathway by itself.
2. A novel GDP/GTP exchanger of RhoA, GEF-H1, has been shown to be a physiological substrate of ERK-
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MAP kinases. Expression of GEF-H1 is up-regulated by the ERK MAP kinase pathway. Phosphorylation of Thr^<678> by ERK-MAP kinases induces the activation of GEF-H1 thereby activates RhoA, whereas it induces the inhibition of Rac1. Furthermore, siRNA-mediated knock down of GEF-H1 enhances the cell motility response. These results suggest that GEF-H1 is involved in the ERK-MAF kinase pathway-mediated cell motility response.
3. c-Jun N-Terminal Kinase (JNK) has been shown to be involved in the regulation of cytokinesis. JNK phosphorylates keratin 8 to induce the relaxation of keratin filaments, which appear to be one of the prerequisites for cells to undergo cytokinesis.
4. Combination of 50 μM PD98059 and a low concentration (3 nM) of vincristin induces marked apoptotic cell death response in G_2/M-phase-arrested T24 cells, but not in G_1-/S-phase-arrested cells. Under such conditions, accumulation of cyclinB, Plk1and Aurora-B has been observed. These results suggest that ERK-MAP Kinase pathway is involved in the regulation of spindle check point. Less
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Report
(3 results)
Research Products
(24 results)
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[Journal Article] Blockade of the phosphatidylinositol 3-kinase-Akt signaling pathway enhances induction of apoptosis by microtubule-destabilizing agents in tumor cells in which the pathway is constitutively activated.2007
Author(s)
Fujiwara, Y., Hosokawa, Y., Watanabe, K., Tanimura, S., Ozaki, K., Kohno, M.
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Journal Title
Mol.Cancer Ther. 6
Pages: 1133-1142
Description
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[Journal Article] Inhibition of the PI3 kinase/Akt pathway enhances doxorubicin-induced apoptotic cell death in tumor cells in a p53-dependent manner.2006
Author(s)
Fujiwara, Y., Kawada, K., Takano, D., Tanimura, S., Ozaki, K., Kohno, M.
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Journal Title
Biochem.Biophys.Res.Commun. 340
Pages: 560-566
Description
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[Journal Article] ERK inhibition slows disease progression in mice with polycystic kidney disease.2006
Author(s)
Omori, S., Hida, M., Fujita, H., Takahashi, H., Tanimura, S., Kohno, M., Awazu, M.
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Journal Title
J.Am.Soc.Nephrol. 17
Pages: 1604-1614
Description
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[Journal Article] Suppression of tumor cell invasiveness by hydrolysable tannins (plant polyphenols) via the inhibition of matrix metalloproteinase-2/-9 activity.2005
Author(s)
Tanimura, S., Kadomoto, R., Tanaka, T., Zhang, Y., Kouno, I., Kohno, M.
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Journal Title
Biochem.Biophys.Res.Commun. 330
Pages: 1306-1313
Description
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[Journal Article] Anticancer drugs up-regulate HspBP1 and thereby antagonize the prosurvival function of Hsp70 in tumor cells.
Author(s)
Tanimura, S., Hirano, A., Hashizume, J., Tasunaga, M., Kawabata, T., Ozaki, K., Kohno, M.
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Journal Title
J.Biol.Chem. (under review)
Description
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