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Studies on mechanism of toxicity of methylmercury

Research Project

Project/Area Number 15209004
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Environmental pharmacy
Research InstitutionTohoku University

Principal Investigator

NAGANUMA Akira  Tohoku University, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学研究科, 教授 (80155952)

Co-Investigator(Kenkyū-buntansha) KUGE Shusuke  Tohoku University, Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院・薬学研究科, 助教授 (50186376)
OHASHI Kazuaki  Osaka University, Graduate School of Pharmaceutical Sciences, Research Associate, 大学院・薬学研究科, 助手 (70344679)
KWANG Gi-Wook  Tohoku University, Graduate School of Pharmaceutical Sciences, Research Associate, 大学院・薬学研究科, 助手 (00344680)
Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥50,700,000 (Direct Cost: ¥39,000,000、Indirect Cost: ¥11,700,000)
Fiscal Year 2005: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
Fiscal Year 2004: ¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000)
Fiscal Year 2003: ¥20,540,000 (Direct Cost: ¥15,800,000、Indirect Cost: ¥4,740,000)
Keywordsmethylmercury / toxicity / resistance / ubiquitin / F-box proteins / Cdc34 / Rad23 / 酵母
Research Abstract

We have identified a gene, CDC34 that confers resistance to methylmercury in Saccharomyces cerevisiae by screening a yeast genomic DNA library. CDC34 encodes one of the ubiquitin-conjugating enzymes (Cdc34) that catalyze ubiquitin transfer onto substrate proteins, an important step for protein degradation via ubiquitin-proteasome pathway. In yeast cells, the ubiquitin-conjugating activity of Cdc34 is essential for the Cdc34-mediated resistance to methylmercury. It is possible to conclude that proteins involved in expression of methylmercury toxicity might exist in the cells and the proteins are degraded after its ubiquitination in proteasomes. In ubiquitin system, substrate proteins are recognized by F-box proteins and ubiquitinated by ubiquitin-conjugating enzymes. Thus, we searched F-box proteins which confer resistance to methylmercury, and found that Hrt3 and Ylr224w have role in protection against methylmercury toxicity. Proteins that bind to these F-box proteins might have activity to intensify the toxicity of methylmercury. We identified three proteins that bind to the F-box proteins, Hrt3 and Ylr224w. Overexpression of the genes for these proteins conferred a hyper susceptibility to methylmercury. Moreover, these proteins are found to be ubiquitinated in the cells. These results suggest that the F-box protein-bounding proteins identified by the present study have significant roles in expression of methylmercury toxicity and are decomposed by the ubiquitin-proteasome pathway. Two of these proteins are enzymes involved in synthesis of pyruvate, and overexpression of these proteins might increase cellular concentration of pyruvate. Addition of excess pyruvate into the culture medium significantly prevents toxicity of methylmercury. Increase in cellular production of pyruvate might have an important role in enhancement of toxicity of methylmercury.

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (13 results)

All 2005 2003

All Journal Article (12 results) Book (1 results)

  • [Journal Article] Overexpression of Rad23 confers resistance to methylmercury in Saccharomyces cerevisiae via inhibition of the degradation of ubiquitinated proteins2005

    • Author(s)
      Hwang, G.W.
    • Journal Title

      Mol. Pharmacol. 68

      Pages: 1074-1078

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Overexpression of Bop3 confers resistance to methylmercury in Saccharomyces cerevisiae through interaction with other proteins such as Fkh1, Rts1 and Msn22005

    • Author(s)
      Hwang, G.W.
    • Journal Title

      Biochem. Biophys. Res. Commun. 330

      Pages: 378-385

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Identification of intracellular factors influenced in sensitivity of cells to methylmercury2005

    • Author(s)
      Naganuma, A.
    • Journal Title

      Proceedings of NMID Forum 2005

      Pages: 75-78

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Overexpression of Rad23 confers resistance to methylmercury in Saccharomyces cerevisiae via inhibition of the degradation of ubiquitinated proteins2005

    • Author(s)
      Hwang, G.W
    • Journal Title

      Mol.Pharmacol. 68

      Pages: 1074-1078

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Overexpression of Bop3 confers resistance to methylmercury in Saccharomyces cerevisiae through interaction with other proteins such as Fkh1, Rts1 and Msn22005

    • Author(s)
      Hwang, G.W
    • Journal Title

      Biochem.Biophys.Res.Commun. 330

      Pages: 378-385

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Toxicity of Mercury2005

    • Author(s)
      Hwang, G.W
    • Journal Title

      The Encyclopedia of Bio-elements (Ed by Hiromu Sakurai) (Ohmsha, Tokyo)

      Pages: 192-196

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Overexpression of Rad23 confers resistance to methylmercury in Saccharomyces cerevisiae via inhibition of the degradation of ubiquitinated proteins2005

    • Author(s)
      Hwang, G.W.
    • Journal Title

      Mol.Pharmacol. 68

      Pages: 1074-1078

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Overexpression of Bop3 confers resistance to methylmercury in Saccharomyces cerevisiae through interaction with other proteins such as Fkh1,Rts1 and Msn22005

    • Author(s)
      Hwang, G.W.
    • Journal Title

      Biochem.Biophys.Res.Commun. 330

      Pages: 378-385

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Overexpression of Bop3 confers resistance to methylmercury in Saccharomyces cerevisiae through interaction with other proteins such as Fkh1, Rts1 and Msn22005

    • Author(s)
      Hwang, G.W.
    • Journal Title

      Biochem.Biophys.Res.Commun. 30(印刷中)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Biological interaction of dietary metals2003

    • Author(s)
      Naganuma, A.
    • Journal Title

      J. Toxicol. Sci. 28

      Pages: 249-249

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Intracellular factors involved in methylmercury toxicity in yeast2003

    • Author(s)
      Naganuma, A.
    • Journal Title

      Proceedings of International Symposium on Bio-Trace Elements 2002

      Pages: 69-70

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Biological interaction of dietary metals2003

    • Author(s)
      Naganuma, A.
    • Journal Title

      J.Toxicol.Sci. 28

      Pages: 249-249

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] 生命元素辞典2005

    • Author(s)
      黄 基旭
    • Total Pages
      440
    • Publisher
      オーム社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary

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Published: 2003-04-01   Modified: 2016-04-21  

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