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Site-specific fragmentation of superoxide dismutase and DNA damage

Research Project

Project/Area Number 06454166
Research Category

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

Allocation TypeSingle-year Grants
Research Field General medical chemistry
Research InstitutionOsaka University

Principal Investigator

TANIGUCHI Naoyuki  Osaka Univ.Med.Sch.Professor, 医学部, 教授 (90002188)

Co-Investigator(Kenkyū-buntansha) SUZUKI Keiichiro  Osaka Univ.Med.Sch.Research Associate, 医学部, 助手 (70221322)
FUJII Junichi  Osaka Univ.Med.Sch.Assistant Professor, 医学部, 講師 (00222258)
Project Period (FY) 1994 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥7,100,000 (Direct Cost: ¥7,100,000)
Fiscal Year 1995: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1994: ¥4,600,000 (Direct Cost: ¥4,600,000)
KeywordsDNA damage / Hydroxyl radical / Cu, Zn-SOD / Mn-SOD / Amyotrophic lateral sclerosis / TGF-beta / Mn-SOD / バキュロウイルス / DNA fragmentation / Glycation / Diabetes / Hydroxy radical / Mutation / FALS
Research Abstract

We have reported that a cytoplasmic protein Cu, Zn-SOD,undergoes glycation, fragmentation, and inactivation under diabetic conditions and aging. We have examined effects of glycated Cu, Zn-SOD on DNA damage. We found that cloned DNA was fragmented by incubation with glycated Cu, Zn-SOD.This fragmentation was also observed in nulcear DNA isolated from cells. Metal ion chelators and hydorxyl radical scavengers inhibited the DNA fragmentation, suggesting the involvement of the Fenton reaction mediated by glycated Cu, Zn-SOD and released Cu^<2+> in this reaction.
We also established human Cu, Zn-SOD expression system using baculovirus and insect cells, and produced three mutant enzymes (Gly41Asp, His43Arg, Gly85Arg) related to amyotrophic lateral sclerosis (ALS) as well as wild-type enzyme and purified them. Gly85Arg mutant exhibited similar activity to the wild-type enzyme, but activities of Gly41Asp and His43Arg were decreased to nearly a half of it. Structural unstability and inactivation of mutant enzymes by hydrogen peroxide may be a cause of the decreased activities, suggesting that ALS may be induced by this decreased activity in mutant enzymes.
A mitochondrial enzyme Mn-SOD is induced by TNF and IL-1 and scavenges reactive oxygen species produced by treatment with cytokines. Our results show that not only Mn-SOD bur also some antioxidative enzymes including Cu, Zn-SOD,catalase, glutathione-S-transferase, are suppressed by treatment with TGF-beta. These results suggest that TGB-beta-induced apoptosis is triggered by the reduction of antioxidative enyzme activities.

Report

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

    (24 results)

All Other

All Publications (24 results)

  • [Publications] M. Asahi: "Inactivation of Glutathione Peroxidase by Nitric Oxide: Implication for Cytotoxicity." J. Biol. Chem.270. 21035-21039 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y. Ikeda: "Involvement of Ser-451 and Ser-452 in the Catalysis of Human γ-Glutamyl Transpeptidase." J. Biol. Chem.270. 22236-22241 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] M. Takahashi: "In Vivo Glycation of Aldehyde Reductase, a Major 3-Deoxyglucosone Reducing Enzyme: Identification of Glycation Sites." Biochemistry. 34. 1433-1438 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] J. Fujii: "Characterization of Wild-type and Amyotrophic Lateral Sclerosis-Related Mutant Cu, Zn-Superoxide Dismutases Overproduced in Baculovirus-Infected Insect Cells." J. Neurochem.64. 1456-1461 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] H. G. Seo: "Induction of Nitric Oxide Synthase and Concomitant Suppression of Superoxide Dismutases in Experimetal Colitis in Rats." Arch. Biochem. Biophys.324. 41-47 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y. Ikeda: "Human γ-Glutamyl Transpeptidase Mutants Involving Conserved Aspartate Residues and the Unique Cysteine Residue of the Light Subunit." J. Biol. Chem.270. 12471-12475 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] M.Asahi: "Inactivation of Glutathione Peroxidase by Nitric Oxide : Implication for Cytotoxicity." J.Biol.Chem.270. 21035-21039 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Ikeda: "Human gamma-Glutamyl Transpeptidase Mutants Involving Conserved Aspartate Residues and the Unique Cysteine Residue of the Light Subunit." J.Biol.Chem.259. 12471-12475 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] M.Takahashi: "In Vivo Glycation of Aldehyde Reductase, a Major 3-Deoxyglucosone Reducing Enzyme : Identification of Geycation Sites." Biochemistry. 34. 1433-1438 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Ikeda: "Involvement of Ser-451 and Ser-452 in the Catalysis of Human gamma-Glutamyl Transpeptidase" J.Biol.Chem.270. 22236-22241 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] J.Fujii: "Characterization of Wild-type and Amyotrophic Lateral Sclerosis-Related Mutant Cu, Zn-Superoxide Dismutases Overproduced in Baculovirus-Infected Insect Cells." J.Neurochem.64. 1456-1461 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] H.G.Seo: "Induction of Nitric Oxide Synthase and Concomitant Suppression of Superoxide Dismutases in Experimetal Colitis in Rats." Arch.Biochem.Biophys.324. 41-47 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] M.Asahi: "Inactivation of Glutathione Peroxidase by Nitric Oxide : Implication for Cytotoxicity." J.Biol.Chem.270. 21035-21039 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Y.Ikeda: "Involvement of Ser-451 and Ser-452 in the Catalysis of Human γ-Glutamyl Transpeptidase." J.Biol.Chem.270. 22236-22241 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] M.Takahashi: "In Vivo Glycation of Aldehyde Reductase,a Major 3-Deoxyglucosone Reducing Enzyme : Identification of Glycation Sites." Biochemistry. 34. 1433-1438 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] J.Fujii: "Characterization of Wild-type and Amyotrophic Lateral Sclerosis-Related Mutant Cu,Zn-Superoxide Dismutases Overproduced in Baculovirus-Infected Insect Cells." J.Neurochem.64. 1456-1461 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] H.G.Seo: "Induction on Nitric Oxide Synthase and Concomitant Suppression of Superoxide Dismutases in Experimetal Colitis in Rats." Arch.Biochem.Biophys.324. 41-47 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Y.Ikeda: "Human γ-Glutamyl Transpeptidase Mutants Involving Conserved Aspartate Residues and the Unique Cysteine Residue of the Light Subunit." J.Biol.Chem.270. 12471-12475 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Kayanoki Y.: "Suppression of antioxidative enzyme expression by transforming growth factor-β1 in rat hepatocytes." J.Biol.Chem.269. 15488-15492 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Fujii J.: "Induction of manganese superoxide dismutase mRNA by okadaic acid and protein synthesis inhibitors." Biochem.J.301. 31-34 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Kaneto H.: "DNA cleavage induced by glycation of Cu,Zn-superoxide dismutase." Biochem.J.304. 219-225 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Ikeda Y.: "Expression of An Active Glycosylated Human γ-Glutamyl Transpeptidase Mutant that Lacks a Membrane Anchor Domain." Proc.Natl.Acad.Sci.USA. 92. 126-130 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Takahashi M.: "In Vivo Glycation of Aldehyde Reductase,a Major 3-Deoxyglucosone Reducing Enzyme:ldentification of Glycation Sites." Biochemistry. 34. 1433-1438 (199)

    • Related Report
      1994 Annual Research Report
  • [Publications] Fujii J.: "Characterization of Wild-type and Amyotrophic Lateral Sclerosis-Related Mutant Cu,Zn-Superoxide Dismutases Overproduced in Baculovirus-lnfected lnsect Cells." J.Neurochem.64(in press). (1995)

    • Related Report
      1994 Annual Research Report

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

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