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2005 Fiscal Year Final Research Report Summary

Mechanism of a arsenic-mediated cancer development

Research Project

Project/Area Number 16310037
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Risk sciences of radiation/Chemicals
Research InstitutionChubu University

Principal Investigator

KATO Masashi  Chubu University, Department of Biomedical Sciences, College of Biomedical Sciences, Professor, 生命健康科学部, 教授 (10281073)

Co-Investigator(Kenkyū-buntansha) KAMBAYASHI Yasuhiro  Kanazawa University, Department of Environmental and Preventive Medicine, Graduate School of Medical Science, Lecturer, 医学系研究科, 講師 (20345630)
OGINO Keiki  Okayama University Graduate School of Medicine, Department of Public Health, Dentistry and Pharmaceutical Sciences, Professor, 医歯薬学研究科, 教授 (70204104)
Project Period (FY) 2004 – 2005
Keywordsarsenic / RET / tyrosine kinase / superoxide dismutase / cancer / superactivation
Research Abstract

More than ten million people in the world suffered drinking water with high concentration of arsenic (>5 mg/1). It is reported that a risk of cancer development in skin, lung, liver or bladder increases in human in epidemiological research. These reports suggest that arsenic is a carcinogen in the human. To prevent against an explosive increase of cancer in the people who drink arsenic-polluted water, we need to clarify the mechanism of arsenic-induced cancer for establishing effective therapies.
The c-RET proto-oncogene encodes a receptor type tyrosine. Ligand of c-RET is glial cell line-derived neurotrophic factor (GDNF), and its signaling is essential for renal organogenesis and enteric neurogenesis. The Ret kinase is activated by point mutations or gene rearrangement. Germ line mutations of the c-RET proto-oncogene are associated with the development of multiple endocrine neoplasia type 2A (MEN2A). Enhancement of oncogenic RET activity through autophosphorylation of tyrosine 905 and tyrosine 1062 are crucially important for transformation.
In this study, we clarified mechanism of arsenic-mediated cancer development through analysis of RET tyrosine kinase activation.
1) Arsenic-mediated superactivation of RET-MEN2A tyrosine kinase.
Arsenic promotes c-RET proto-oncogene product activity (c-RET protein tyrosine kinase). Arsenic superactivates kinase activity of RET oncogene product (RET-MEN2A: c-RET with cysteine 634 replaced arginine), in which kinase activity was 3-10 fold augmented by genetic mutation.
2) Arsenic promoted autophosphorylation of key tyrosines for activation in c-RET.
Autophosphorylation of tyrosines 905 and 1062 were reported to be crucially important for c-RET kinase activation. Arsenic promoted autophosphorylation of 905 and 1062 tyrosines in c-RET.
3) Effect of SOD1 (superoxide dismutase 1) on arsenic-mediated RET kinase activation.
We showed that SOD1 inhibited UV-mediated but not arsenic-mediated RET tyrosine kinase activity.

  • Research Products

    (11 results)

All 2006 2005 2004

All Journal Article (10 results) Book (1 results)

  • [Journal Article] A PKC-mediated backup mechanism of the MXXCW motif-linked switch for initiating tyrosine kinase activities.2006

    • Author(s)
      Takeda K, Kato M (4/8), et al.
    • Journal Title

      FEBS Letters 580

      Pages: 839-843

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] 環境因子はどのようなメカニズムで悪性腫瘍を誘発するのか : 動物モデルでの解析2006

    • Author(s)
      加藤昌志(1/1)
    • Journal Title

      中部大学生命健康科学研究所紀要 1

      Pages: 1-8

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] A PKC-mediated backup Mechanism of the MXXCW motif-linked switch for initiating tyrosine kinase activities.2006

    • Author(s)
      Takeda K, Kato M (4/8), et al.
    • Journal Title

      FEBS Letters 580

      Pages: 839-843

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Redox control of catalytic activities of membrane-associated protein2005

    • Author(s)
      Nakashima I, Kato M (5/6), et al.
    • Journal Title

      Arch Biochem Biophys 434

      Pages: 3-10

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Interleukin-6 gene ablation in a transgenic mouse model of malignant skin melanoma.2005

    • Author(s)
      von Felbert V, Kato M(5/8) et al.
    • Journal Title

      Am J Pathol 166

      Pages: 831-841

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] 5-aminolaevulinic acid photodynamic therapy in a transgenic mouse model of skin melanoma2005

    • Author(s)
      Cordoba F, Kato M (5/7), et al.
    • Journal Title

      Exp Dermatology 14

      Pages: 429-437

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Mechanism of environmental factor-induced cancer in animal model2005

    • Author(s)
      Kato M.
    • Journal Title

      Proceeding of the Research Institute of Life and Health Sciences in Chubu University 1

      Pages: 1-8

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Redox control of catalytic activities of membrane-associated protein.2005

    • Author(s)
      Nakashima I, Kato M (5/6), et al.
    • Journal Title

      Arch Biochem Biophys 434

      Pages: 3-10

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Interleukin-6 gene ablation in a transgenic mouse model of malignant skin melanoma.2005

    • Author(s)
      von Felbert V, Kato M(5/8) et al.
    • Journal Title

      Am J Pathol. 166

      Pages: 831-841

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] A novel RFP-RET transgenic mouse model with abundant eumelanin in the cochlea.2004

    • Author(s)
      Hayashi H, Kato M (5/7), et al.
    • Journal Title

      Hear Res 195

      Pages: 35-40

    • Description
      「研究成果報告書概要(和文)」より
  • [Book] 免疫学実験法ハンドブック2006

    • Author(s)
      中島, 加藤ら[中島泉 編]
    • Total Pages
      358
    • Publisher
      名古屋大学出版会
    • Description
      「研究成果報告書概要(和文)」より

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Published: 2008-05-27  

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