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Role of actin-regulatory gelsolin in control of cell growth

Research Project

Project/Area Number 06044009
Research Category

Grant-in-Aid for international Scientific Research

Allocation TypeSingle-year Grants
SectionJoint Research
Research InstitutionHokkaido University

Principal Investigator

KUZUMAKI Noboru  Hokkaido University School of Medicine Professor, 医学部, 教授 (80091445)

Co-Investigator(Kenkyū-buntansha) MCLAUGHLIN Paul  Cambridge Medical Research Council Research Scientist, 研究員
JANMEY Paul  Harvard Medical School Associate Professor, 医学部, 準教授
STOSSEL Thomas  Harvard Medical School Professor, 医学部, 教授
FUJITA Hisakazu  Hokkaido University School of Medicine Lecturer, 医学部, 助手 (30212187)
Project Period (FY) 1994 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥11,200,000 (Direct Cost: ¥11,200,000)
Fiscal Year 1995: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 1994: ¥5,700,000 (Direct Cost: ¥5,700,000)
KeywordsActin / Gelsolin / Cell growth / Tumor suppression / Mutants / Bladder cancer / Colon cancer / ラス癌遺伝子 / フォスホリパーゼ / PIP_2 / NIH / 3T3 / DNA合成 / 胃癌
Research Abstract

1. We cloned a mutant gelsolin cDNA His321 from the flat revertant R1 of human activated Ha-ras oncogene-transformed NIH3T3 fibroblasts (EJ-NIH3TS). His321 suppressed tumorigenicity of EJ-NIH3T3. We expressed the His321 and wild-type gelsolin in Escherichia coli, purified them, and analyzed their effects on actin, polyphosphoinositol lipids and phospholipase C.His321 decreased actin-filament-severing activity and increased nucleating activity compared with wild-type gelsolin in vitro. Furthermore, compared to wild-type gelsolin both nucleation and severing by His321 were inhibited more strongly by the phosphoinositol lipids phosphatidylinositol 4-phosphate (PtdInsP) and phosphatidylinositol 4,5-bisphosphate (PtdInsP2). In addition, His321 inhibited PtdInsP2 hydrolysis by phospholipase C gamma 1 more strongly than wild-type gelsolin in vitro because of its higher binding capacity for phosphoinositol Lipid. Our results suggest that the segment G3 of gelsolin which contains the mutation i … More s functionally relevant for regulation of gelsolin's activities and that the region around the residue 321 may contain a phosphoinositol-lipid-binding site. Altered functions of His321 gelsolin might be important for the loss of tumorigenicity of the ras-transformed cells.
2. We examined the expression of gelsolin in a number of human bladder and colon cancer cell lines and tissues. In all 6 bladder and 6 of 7 colon cancer cell lines and in 14 of the 18 bladder(77.8%)and 9 of 18 colon(50%)tumor tissues, gelsolin expression was undetectable or extremely low in comparison with its expression in normal bladder or colon epithelial cells. Furthermore, upon the introduction of the exogenous human or mouse authentic gelsolin cDNA into a human bladder cancer cell line UMUC-2 or a human colon cancer cell line LoVo, gelsolin transfectants of UMUC-2 and LoVo greatly reduced the colony-forming ability and the tumorigenicity in vivo. These results suggest that gelsolin plays a key role as a tumor suppressor in human urinary bladder and colon carcinogenesis. Less

Report

(2 results)
  • 1995 Final Research Report Summary
  • 1994 Annual Research Report
  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] Fujita,H.ほか: "Functions of mutated gelsolin,His321 isolated from a flat revertant of ras-transformed cells." Eur.J.Biochem.229. 615-620 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ishizaki,A.ほか: "Growth inhibitory functions of a mutated gelsolin (His321) in NIH/3T3 mouse fibroblasts." Exp.Cell Res.217. 448-452 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Tanaka,M.ほか: "Gelsolin : a candidate for suppressor of human bladder cancer." Cancar Res.55. 3228-3232 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Furuuchi,K.ほか: "Growth inhibition of human colon carcinoma cells by gelsolin cDNA transfer." Tumor.Targeting.(in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Fujita,H.ほか: "Inhibitory mutant of gelsolin severing activity." FEBS.Letter.(in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Fujita, H.: "Functions of mutated gelsolin, His321 isolated from a flat revertant of ras-transformed cells." Eur. J.Biochem.229. 615-620 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Ishizaki, A.: "Growth inhibitory functions of a mutated gelsolin (His321) in NIH/3T3 mouse fibroblasts." Exp. Cell Res.217. 448-452 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Tanaka, M.: "Gelsolin : a candidate for suppressor of fuman bladder cancer" Cancer Res.55. 3228-3232 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Furuuchi, K.: "Growth inhibition of human colon carcinoma cells by gelsolin cDNA transfer." Tumor. Targeting.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Fujita, H.: "Inhibitory mutant of gelsolin severing activity." FEBS.Letter.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Fujita, H. ほか: "Enhanced inhibitory effect of the mutated gelsolin His321 on phospolipase Cγ_1." Cell Structure and Function. 18. 591 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Moriya, S. ほか: "Differential expression on HSP 90, gelsolin and GST-π in human gastric carcinoma cell lines." Int. J. Oncology.5. 1347-1351 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Ishizaki, A. ほか: "Growth inhibitory functions of a mutated gelsolin (His321) in NIH/3T3 mouse fibroblasts." Exp. Cell Res.(印刷中). (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] Fujita, H. ほか: "Functions of mutated gelsolin, His321 isolated from a flat revertant of ras-transformed cells." Eur. J. Biochem.(印刷中). (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] 葛巻 暹、藤田寿一: "アクチン結合蛋白質と細胞増殖制御." 蛋白質核酸酵素. 39. 212-220 (1994)

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2016-04-21  

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