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Studies on the mechanism of NDP kinase/nm23 and its interacting proteins

Research Project

Project/Area Number 10470489
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionTokyo Metropolitan Institute of Gerontology

Principal Investigator

KIMURA Narimichi  Tokyo Metropolitan Institute of Gerontology, Gene Regulation & Protein Function, Head, 遺伝子情報部門, 部長 (60073029)

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)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
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)
KeywordsNDP kinase / nm23 / Signal transduction / Cell growth / Differentiation / Metastasis suppressor / 酵素活性 / PC12細胞 / 神経突起形成 / NGF / dbcAMP
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 … More 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

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report

Research Products

(35 results)

All Other

All Publications

  • [Publications] Kimura.N.,Shimada,N., et al.: "Regulation of cellular functions by nucleoside diphosphate kinases in mammals."J.Bioenerg.Biomemb.,. 32. 309-315 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Orlov,N.Ya.,Orlova,T.G., et al.: "Comparative study of recombinant nucleoside diphosphate kinases α and β by intrinsic protein fluorescence."J.Biomol.Struc.Dynam.. 16. 955-968 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishijima,Y.,Shimada,N., et al.: "Overexpression of nucleoside diphosphate kinases induces neurite outgrowth and their substitution to inactive forms leads to suppression of nerve growth factor- and dibutyryl cyclic AMP-induced effects in PC12D cells."FEBS Lett.,. 455. 155-159 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Miyazaki,H.,Fukuda,M., et al.: "Overexpression of nm23-H2/NDP kinase B in a human oral squamous cell carcinoma cell line results in reduced metastasis, differentiated phenotype in the metastatic site and growth factor-independent proliferative activity in culture."Clin.Cancer Res.,. 5. 4301-4307 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Orlov,N.Ya.and Kimura,N.:: "Interaction of nucleoside diphosphate kinase with membranes of bleached bovine retinal rod outer segments. Effects of pH, salts and guanine nucleotides. "Biochemistry (Moscow). 63. 171-179 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yasutomo,Y.,Ishikawa,N., et al.: "Nucleoside diphosphate kinase in fetal rat bone tissue : Increased expression in osteoblasts and localization in matrix vesicle fraction."J.Bone Mineral Metab.. 16. 215-226 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 木村成道 他2名 編著: "光シグナルトランスダクション"シュプリンガー・フェアラーク東京. 195 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Toda, T., Kaji, K.and Kimura, N.: "TMIG-2DPAGE : A new concept of two-dimensional gel protein database for research on aging"Electrophoresis. 19. 344-348 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Toda, T., Satoh, M., Sugimoto, M., Goto, M., Furuichi, Y.and Kimura, N.: "A comparative analysis of the proteins between the fibroblasts from Wemer's syndromepatients and age-matched normal individuals using two-dimensional gel electrophoresis"Mech. Ageing Dev.. 100. 133-143 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Orlov, N.Ya. and Kimura, N.: "Interaction of nucleoside diphosphate kinase with membranes of bleached bovine retinal rod outersegments. Effects of pH, salts and guanine nucleotides."Biochemistry (Moscow). 63. 171-179 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kimura, N., Tomizawa, S., Nakata, K.and Kimura, N.: "Chronic treatment with estrogen up-regulates expression of sst2 messenger ribonucleic acid (mRNA) but down-regulates expression of sst5 mRNA in rat pituitaries."Endocrinology. 139. 1573-1580 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yasutomo, Y., Ishikawa, N., Nagata, N.and Kimura, N.: "Nucleoside diphosphate kinase in fetal rat bone tissue : Increased expression in osteoblasts and localization in matrix vesicle fraction."J.Bone Mineral Metab.. 16. 215-226 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Orlov, N.Ya., Orlova, T.G., Reshetnyak, Y.K., Burstein, E.A.and Kimura, N.: "Comparative study of recombinant nucleoside diphosphate kinases α and β by intrinsic protein fluorescence."J.Biomol. Struc. Dynam.. 16. 955-968 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishijima, Y., Shimada, N., Fukuda, M., Miyazaki, H., Orlov, N.Ya., Orlova, T.G., Yamada, T.and Kimura, N.: "Overexpression of nucleoside diphosphate kinases induces neurite out-growth and their substitution to inactive forms leads to suppression of nerve growth factor-FEBS Lett."445. 155. 159 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Miyazaki, H., Fukuda, M., Ishijima, Y., Takagi, Y., Iimura, T., Negishi, A., Hirayama, R., Ishikawa, N., Amagasa, T.and Kimura, N.: "Overexpression of nm23-H2/NDP kinase B in a human oral squamous cell carcinoma cell line results in reduced metastasis, differentiated phenotype in the metastatic site and growth factor-independent proliferative activity in culture."Clin. Cancer Res.. 5. 4301-4307 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Toda, T., Sugimoto, M., Omori, A., Matsuzaki, T., Furuichi, Y.and Kimura, N.: "Proteomic anolysis of immortalization of Epstein-Barr virus-transformed human B-lymphoblastoid cell lines."Electrophoresis. 21. 1814-1822 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kimura, N., Shimada, N., Fukuda, M., Ishijima, Y., Miyazaki, H., Ishii, A., Takagi, Y.and Ishikawa, N.: "Regulation of cellular functions by nucleoside diphosphate kinases in mammals"J.Bioenerg. Biomemb.. 32. 309-315 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Roymans, D., Vissenberg, K., De Jonghe, C., Willems, R., Engler, G., Kimura, N., Grobben, B., claes, P., Verbelen, J-P., Broeckhoven, C.V., and Slegers, H.: "Identification of the tumor metastasis suppressor nm23-H1 as a component of the centrosome."Exp. Cell Res.. 262. 145-153 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kimura, N., Tomizawa, S., Nakata-Arai, K., Osamura, R.Y., and Kimura, N.: "Characterization of 5-flanking region of rat somatostatin receptor sst2 gene : transcriptional regulatory elements, and activation by Pitx1 and estrogen."Endocrinology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Toda,T. et al: "Proteomic anolysis of immortalization of Epstein-Barr virus-transformed human B-lymphoblastoid cell lines."Electrophoresis. 21. 1814-1822 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kimura,N. et al: "Regulation of cellular functions by nucleoside diphosphate kinases in mammals."J.Bioenerg.Biomemb.. 32. 309-315 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Roymans,D. et al: "Identification of the tumor metastasis suppressor nm23-H1 as a component of the centrosome."Exp.Cell Res.. 262. 145-153 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kimura,N. et al.: "Characterization of 5'-flanking region of rat somatostatin receptor sst2 gene : transcriptional regulatory elements, and activation by Pitx1 and estrogen."Endocrinology. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Orlev, N. Ya. et al.: "Comparative study of recombinant nucleoside diphosphate Kinases α and β by intrinsic protein fluorescence"J. Biomol. Struc. Dynam.. 16. 955-968 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ishijima, Y. et al.: "Overexpression of nucleoside diphosphate kinases induces neurite outgrowth and their substitution to inactive forms leads to suppression of nerve growth factor-and dibutyryl cyclic AMP-inducted effects in PC12D cells"FEBS Lett.. 445. 155-159 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Miyazaki, H. et al.: "Overexpression of nm23-H2/NDP Kinase B in a human oral squamous cell carcinoma cell line results in reduced metastasis, differentiated phenotype in the metastic site and growth factor-independent proliferative activity in culture"Clin. Cancer Res.. 5. 4301-4307 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Toda, T. et al.: "Proteomic anolysis of immortalization of Epstein-Barr virus-transformed human Blymphoblastoid cell lines"Electrophoresis. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Kimura, N. et al.: "Regulation of cellular functions by nucleoside diphosphate kineses in mammals"J. Bioenerg. Biomemb. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] 蓮沼仰嗣 木村成道 徳永史生編著: "光シグナルトランスダクション"シュプリンガー・フェアラーク東京. 195 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 木村成道(代表者): "短期プロジェクト研究報告書「多機能性蛋白質による細胞機能の調節と老化」"財団法人 東京都老人総合研究所. 90 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Orlov,N.& Kimura,N.: "Interaction of nucleoside diphosphate kinase with membranes of bleached bovine retinal rod outer segments.Effects of pH,salts and guanine nucleotides." Biochemistry(Moscow). 63. 171-179 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yasutomo,Y.et al.: "Nucleoside diphosphate kinase in fetal rat bone tissue:Increased expression in osteoblasts and localization in matrix vesicle fraction." J.Bone Mineral Metab.16. 215-226 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Orlov,N.et al.: "Comparative study of recombinant nucleoside diphosphate kinases α and β by intrinsic protein fluorescence." J.Biomol.Struc.Dynam.16. in press (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ishijima,Y.et al.: "Overexpression of nucleoside diphosphate kinases induces neurite outgrowth and their substitution to inactive forms leads to suppression of nerve growth factor-and dibutyryl cyclic AMP-induced effects in PC12D cells." FEBS Lett.445. 155-159 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] 木村成道: "癌の転移" 図説 分子病態学(第2版)(一瀬,鈴木編). 224-228 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-03-31   Modified: 2016-04-21  

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