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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)
中島 泉  中部大学, 生命健康科学研究所, 教授 (40022826)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥6,900,000 (Direct Cost: ¥6,900,000)
Fiscal Year 2005: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2004: ¥3,600,000 (Direct Cost: ¥3,600,000)
Keywordsarsenic / RET / tyrosine kinase / superoxide dismutase / cancer / superactivation / 発癌機構 / アミノ酸 / スーパーオキサイド / 癌遺伝子産物 / ERK / ゼラチン分解酵素
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.

Report

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

    (22 results)

All 2006 2005 2004

All Journal Article (20 results) Book (2 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
    • Related Report
      2005 Final Research Report Summary
  • [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

    • NAID

      110004622806

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [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
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A PKC-mediated backup mechanism of the MXXCW motif-linked switch for initiating tyrosine kinase activities.2006

    • Author(s)
      Takeda K
    • Journal Title

      FEBS Letters

      Volume: 580 Pages: 839-43

    • Related Report
      2005 Annual Research Report
  • [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
    • Related Report
      2005 Final Research Report Summary
  • [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
    • Related Report
      2005 Final Research Report Summary
  • [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
    • Related Report
      2005 Final Research Report Summary
  • [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

    • NAID

      110004622806

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

    • Author(s)
      von Felbert V
    • Journal Title

      Am J Pathol

      Volume: 166 Pages: 831-41

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 5-aminolaevulinic acid photodynamic therapy in a transgenic mouse model of skin melanoma.2005

    • Author(s)
      Cordoba F
    • Journal Title

      Exp Dermatology

      Volume: 14 Pages: 429-37

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Redox control of catalytic activities of membrane-associated protein tyrosine kinases.2005

    • Author(s)
      Nakashima I
    • Journal Title

      Arch Biochem Biophys

      Volume: 434 Pages: 3-10

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Redox control of catalytic activities of membrane-associated protein2005

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

      Arch Biochem Biophys

      Volume: 434 Pages: 3-10

    • Related Report
      2004 Annual Research Report
  • [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

      Volume: 166 Pages: 831-841

    • Related Report
      2004 Annual Research Report
  • [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
    • Related Report
      2005 Final Research Report Summary
  • [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

      Volume: 195 Pages: 35-40

    • Related Report
      2004 Annual Research Report
  • [Journal Article] c-Kit-targeting immunotherapy for hereditary melanoma in amouse2004

    • Author(s)
      Kato M (1/12), et al.
    • Journal Title

      cancer Res

      Volume: 64 Pages: 801-806

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Spontaneous vitiligo in an animal model for human melanoma : Role of tumorspecific CD8+ T cells.2004

    • Author(s)
      Lengagne R, Kato M (6/12), et al.
    • Journal Title

      Cancer Res

      Volume: 64 Pages: 1496-1501

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Identification of RET Autophosphorylation Sites by Mass Spectrometry.2004

    • Author(s)
      Kawamoto Y, Kato M (7/10), et al.
    • Journal Title

      J Biol Chem

      Volume: 279 Pages: 14213-14224

    • Related Report
      2004 Annual Research Report
  • [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
    • Related Report
      2005 Final Research Report Summary
  • [Book] Prog Protein Res2005

    • Author(s)
      Nakashima I, Kato M (5/6), et al.
    • Publisher
      MXXCW motif as a potential initiator of protein tyrosine kinases.(印刷中)
    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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