| Project/Area Number |
10470489
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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 | Tokyo Metropolitan Institute of Gerontology |
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Principal Investigator |
KIMURA Narimichi Tokyo Metropolitan Institute of Gerontology, Gene Regulation & Protein Function, Head, 遺伝子情報部門, 部長 (60073029)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIKAWA Naoshi Tokyo Metropolitan Institute of Gerontology, Gene Regulation & Protein Function, Res. Scient., 遺伝子情報部門, 研究員 (30184485)
FUKUDA Mitsugu Tokyo Metropolitan Institute of Gerontology, Gene Regulation & Protein Function, Res. Assoc., 遺伝子情報部門, 助手 (30100126)
SHIMADA Nobuko Tokyo Metropolitan Institute of Gerontology, Gene Regulation & Protein Function, Res. Assoc., 遺伝子情報部門, 助手 (60158962)
MATSUZAKI Takao Mitsubishi Chem. Co. Yokohama Inst., Fellow (Leader), 横浜総合研究所, 部長
NOMURA Kohji Tokyo Metropolitan Institute of Gerontology, Protein Biochemistry, Res. Scient., 蛋白質生化学部門, 研究員 (30073026)
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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 |
¥12,700,000 (Direct Cost: ¥12,700,000)
Fiscal Year 2000: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1999: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 1998: ¥5,600,000 (Direct Cost: ¥5,600,000)
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| Keywords | NDP kinase / nm23 / Signal transduction / Cell growth / Differentiation / Metastasis suppressor / 酵素活性 / PC12細胞 / 神経突起形成 / NGF / dbcAMP |
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| Research Abstract |
The role of nucleoside diphosphate (NDP) kinases in cell growth, differentiation, and tumor metastasis was investigated. The essential role of NDP kinase in cell growth was validated by coupling between reduced NDP kinase levels induced by antisense oligonucleotides and the suppression of proliferative activity of a cultured cell line. On the other hand, the enhanced NDP kinase accumulation was demonstrated in the matured osteoblasts in vivo and in vitro by immunohistochemistry. In PC12D cells, neurite outgrowth took place in NDP kinase β-transfected clones without differentiation induders, which was accompanied by prologation of doubling time. Neurite outgrowth triggered by nerve growth factor and a cyclic AMP analog was down-regulated upon forced expression of inactive mutant NDP kinase by virtue of a dominant negative effect. NDP kinase α-transfected rat mammary adenocarcinoma cells (MTLn3) and nm23-H2-transfected human oral squamous cell carcinoma cells (LMF4) manifested reduced me
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tastatic potential and were associated with an altered sensitivity to environmental factors such as motility and growth factors. Considering the housekeeping nature of NDP kinases, it is plausible that there is a mechanism that keeps NDP kinase protein levels constant to maintain their function in a variety of cells. To investigate this problem, we employed a tetracycline-controlled expression system allowing the expression of exogenously introduced NDP kinase in a tetracyclin-dependent manner in a cell and attempted to determine whether endogenous NDP kinase protein levels are affected by the expression of exogenous NDP kinase. The results demonstrated that the endogenous NDP kinase levels are suppressed by the co-expression of exogenous NDP kinase, implying the presence of a negative feedback regulation of NDP kinase genes by their protein products. Taken together, NDP kinase isoforms appear to elicit both their own respective and common effects. They may have an ability to lead cells to both proliferative and differentiated states by modulating responsiveness to environmental factors, but their fate seems to depend on their surrounding milieu. Less
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