• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Study of the molecular mechanisms of cell death induced by the dNTP pool imbalance.

Research Project

Project/Area Number 08457607
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionOkayama University

Principal Investigator

WATAYA Yusuke  Okayama University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (90127598)

Co-Investigator(Kenkyū-buntansha) ARAI Meiji  Okayama University, Faculty of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (30294432)
Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥7,700,000 (Direct Cost: ¥7,700,000)
Fiscal Year 1997: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1996: ¥6,100,000 (Direct Cost: ¥6,100,000)
Keywordsapoptosis / cell death / DNA strand break / intracellular acidification / protease / endonuclease / necrosis / antitumor agent / DUA鎖切断 / 5-fluoro-2′-deoxyuridine / 制ガン剤
Research Abstract

We have investigated the molecular mechanism of cell death induced by 5-fluoro-2'-deoxyuridine (FUdR). FUdR caused cell death to induce dNTP pool imbalance and following DNA double strand breaks in mouse mammary tumor FM3A cells. We observed that protease inhibitors (such as TLCK,TPCK,PMSF,p-APMSF,Pefabloc SC,and Z-Asp-CH_2-DCB) blocked intracellular acidification, DNA fragmentation, and FUdR-induced cell death. We also revealed that FUdR-induced death of FM3A cells was found to be associated with an increased expression of cellular c-jun and c-fos genes. The increases in these gene expressions was mediated through the protein kinase C-dependent pathway. Blockage of the expression with the use of antisense oligodeoxynucleotide for c-jun delayd the cell death. These findings suggest that the activation of c-jun and c-fos genes, which encode transcription factors participating in cell proliferation, plays a role in FUdR-induced cell death. We have also found that mode of cell death induced by FUdR changed in wild-type F28-7 clone of FM3A cells after six-month culture. In the original stocked F28-7 clone, FUdR-induced cell death was accompanied by necrosis-like cell swelling and DNA fragmentation to 100-200 kbp with no evidence of associated oligonucleosomal DNA fragmentation. In subclone F28-7-A isolated from F28-7 cells which were cultured for six months, apoptotic bodies and nucleosomal DNA-ladder fragments were observed. Furthemore, we revealed additional findings that at 24 h after treatment with FUdR,caspase-3-like activity increased 24-fold in F28-7 cells and 5.3-fold in F28-7-A cells. Inhibitors of caspases and serine proteases suppressed FUdR-induced cell death and the increase in caspase-3-like activity in both clones. Investigation of differences in mode of cell death between these clones would be important to elucidate the molecular mechanism of pivotal role in deciding subsequent fates of cells toward either apoptosis or necrosis.

Report

(3 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Toshifumi Kakutani: "Activation of c-fos and c-jun genes and protease association in cell death induced with 5-fluoro-2'-deoxyuridine in mouse mammary tumor FM3A cell line." Nucleic Acids Symp.Ser.35. 269-270 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Shiro Kankawa: "The endonuclase S relative to dNTP imbalance death." Nucleic Acids Symp.Ser.35. 271-272 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 綿矢 有佑: "アポトーシスとエンドヌクレアーゼ" 血液・免疫・腫瘍. 1. 282-287 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Akio Nagano: "The Molecular Mechanisms of 5-Fluoro-2'-Deoxyuridine Induced Cell Death." Nucleic Acids Symp.Ser.37. 135-136 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hiroshi Kanda: "Cytotoxic Mechanisms of New Antitumor Nucleoside Analogues,3'-Ethynylcytidine(ECyd) and 3'-Ethynyluridine(EUrd)." Nucleic Acids Symp.Ser.37. 137-138 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Toshifumi Kakutani: "Activation of c-fos and c-jun Genes in dNTP Imbalance Cell Death Induced with 5-Fluoro-2'-deoxyuridine in Mouse Mammary Tumor FM3A Cell Line." Nucleosides & Nucleotides. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Minoru Nakamura: "Deoxyribonucleoside Triphosphates in Mouse Fetal Liver Cells Assayed by High Pressure Liquid Chromatography." Toxicology Methods. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Satoshi Takatori: "The Characterization of Cell Death Induced by 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine(ECyd) on FM3A Cells." Nucleosides & Nucleotides. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Toshifumi Kakutani et al.: "Activation of c-fos and c-jun genes and protease association in cell death induced with 5-fluoro-2'-deoxyuridine in mouse mammary tumor FM3A cell line." Nucleic Acids Symp.Ser.35. 269-270 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Shiro Kankawa et al.: "The endonuclase S relative to dNTP imbalance death." Nucleic Acids Symp.Ser.35. 271-272 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Yusuke Wataya et al.: "Apoptosis and endonuclease. (Japanese)" Blood・Immunity・Cancer. 1. 282-287 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Akio Nagano et al.: "The molecular mechanisms of 5-fluoro-2'-deoxyuridine induced cell death." Nucleic Acids Symp.Ser.37. 135-136 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hiroshi Kanda et al.: "Cytotoxic mechanisms of new antitumor nucleoside analogues, 3'-ethynylcytidine (ECyd) and 3'-ethynyluridine (EUrd)." Nucleic Acids Symp.Ser.37. 137-138 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Toshifumi Kakutani et al.: "Activation of c-fos and c-jun genes in dNTP imbalance cell death induced with 5-fluoro-2'-deoxyuridine in mouse mammary tumor FM3A cell line." Nucleosides & Nucleotides. (in press.).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Minoru Nakamura et al.: "Deoxyribonucleoside triphosphates in mouse fetal liver cells assayd by high pressure liquid chromatography." Toxicology Methods. (in press.).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Satoshi Takatori et al.: "The characterization of cell death induced by 1- (3-C-ethynyl-beta-D-ribo-pentofuranosyl) cytosine (ECyd) on FM3A cells." Nucleosides & Nucleotides. (in press.).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] A.Nagano: "The Molecular Mechanisms of 5-Fluoro-2'-Deoxyuridine Induced Cell Death." Nucleic Acids Symposium Series.37. 135-136 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] H.Kanda: "Cytotoxi Mechanisms of New Antitumor Nucleoside Analogues,3'-Ethynylcytidine (ECyd) and 3'-Ethynyluridine (EUrd)." Nucleic Acids Symposium Series.37. 137-138 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] T.Kakutani: "Activation of c-fos and c-jun Genes in dNTP Imblance Cell Deth Induced with 5-Fluoro-2'-deoxyuridine in Mouse Mammary FM3A Cell Line." Nucleoside.Nucleotide.(印刷中).

    • Related Report
      1997 Annual Research Report
  • [Publications] M.Nakamura: "Deoxyribonucleoside Triphosphates in Mouse Fetal Liver Cells Assayed by High Pressure Liquid Chromatograpy." Toxicology Methods. (印刷中).

    • Related Report
      1997 Annual Research Report
  • [Publications] S.Takatori: "The Characterization of Cell Death Induced by 1-(3-C-ethynyl-b-ribopentofuranosyl) cytosine (Ecyd) on FM3A Cells." Nucleoside.Nucleotide. (印刷中).

    • Related Report
      1997 Annual Research Report
  • [Publications] 綿矢有佑: "アポトーシスとエンドヌクレアーゼ" 血液・免疫・腫瘍. 1. 282-287 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] T.Kalutani: "Activation of c-fos and c-jun genes,and protease association in cell death induced with 5-fluoro-2′-deoxyuridine in mouse mammary tumor FM3A cell line" Nucleic Acide Symposium Series. 35. 269-270 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] S.Kankawa: "The endonuclease Srelative to dNTP imbalance death" Nucleic Acids Symposium Series. 35. 270-271 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] S.Takatori: "Antitumor mechanism of 3′-ethynylcytidine (ECyd) and 3′-ethynyluridine (EUrd)" Nucleic Acids Symposium Series. 35. 209-210 (1996)

    • Related Report
      1996 Annual Research Report

URL: 

Published: 1996-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi