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2001 Fiscal Year Final Research Report Summary

Analysis of the mechanism of ultraviolet irradiation-mediated induction skin malignant melanoma

Research Project

Project/Area Number 12670816
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Dermatology
Research InstitutionNagoya University

Principal Investigator

NAKASHIMA Izumi  Graduate School of Medicine, Nagoya University Professor, 大学院・医学研究科, 教授 (40022826)

Co-Investigator(Kenkyū-buntansha) SUZUKI Haruhiko  Graduate School of Medicine, Nagoya University Associate Professor, 大学院・医学研究科, 助教授 (90283431)
Project Period (FY) 2000 – 2001
KeywordsRET oncogene / RET-transgenic mice / ultraviolet / malignant / malignant melanoma / melanocytic tumors / oxidative stress / anti-oxidants
Research Abstract

We previously established three lines of RET oncogene-transgenic mice. In all of these three lines of transgenic mice skin melanosis developed soon after birth. Melanocytic tumors developed in lines 304 and 192 but not in line 242 during ageing. Malignant skin melanoma also developed in line 304 which had been crossed repeatedly with C57BL (line 304/B6), but not in line 192. Using these transgenic mouse lines, we analyzed the mechanism of ultraviolet irradiation-mediated induction of skin malignant melanoma. When line 192 of transgenic mice were irradiated repeatedly with ultraviolet light for 7 months skin, malignant melanoma developed. Ultraviolet irradiation of line 242 of transgenic mice, however, did not induce the development of melanocytic tumors. These results suggested that ultraviolet irradiation affects the step of tumor promotion from benign to malignant but not the step of the initial development of tumor. We then showed that ultraviolet irradiation of either RET-transgenic mice or NIH3T3 cells that carried RET oncogene induced activation of RET kinase. The mechanism of activation of RET kinase by ultraviolet irradiation was then examined. Mutant RETs in which each of the conserved cysteine residues in the kinase domain was replaced with alanine were prepared, and the levels of catalytic activity and reactivity to ultraviolet irradiation required for augmention of the activity of these mutant RETs were measured. We found in this study that structural modification through oxidation of a conserved cysteine residue (Cys-987 of c-RET) causes dimerization or polymerization of RET antigens, which accompanies an increase in catalytic activity of RET. It was speculated from these results that ultraviolet irradiation, which is long known to injure DNA and membrane lipid, also affects proteins for modification of structure and function and this mechanism plays a role in the promotion of benign melanocytictumors to malignant melanoma.

  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Kato, M.: "Ultraviolet radiation induces both full activation of Ret kinase and malignant melanocytic tumor promotion in RFP-RET-transgenic mice"J. Invest. Dermatol.. 115. 1157-1158 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kato, M.: "Molecular mechanism of activation and superactivation of Ret tyrosine kinases by ultraviolet light irradiation"Antioxidants & Redox Signaling. 2. 841-849 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kato, M.: "Ultraviolet inudces redox reaction-mediated dimerization and superactivation of oncogenic Ret tyrosine kinases"Mol. Biol. Cell. 11. 93-101 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Dal, Y.: "T-cell-immunity-based inhibitory effects of orally administered herbal medicine juzen-taiho-to on the growth of primarily developed melanocytic tumors in RET-transgenic mice"J. Invest. Dermatol.. 117. 694-701 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kato, N.: "Repair by Src Kinase of Function-Impaired RET-MEN2A with Mutations at Tyrosines in the Carboxyterminal Kinase Domain"Cancer Res.. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kato, M.: "RET tyrosine kinase enhances hair growth in association with promotion of melanogenesis"Oncogene. 20. 7536-7541 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 吉川敏一(編集): "酸化ストレス-フリーラジカル医学生物学の最前線"医歯薬出版. 326 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kato, M, Liu, W., Akhand, A.A., Hossain, K., Takeda, K., Takahashi, M., Nakashima, I.: "Utraviolet radiation induces both full activation of Ret kinase and malignant melanocytic tumor promotion in RFP-RET-transgenic mice"J. Invest. Dermatol. 115. 1157-1158 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kato, M., Iwashita, T., Akhaad, A.A., Liu, W., Takeda, K., Takeuchi, K., Yoshihara, M., Hossain, K., Wu, J., Du, J., Oh, C., Kawamoto, Y., Suzuki, K., Takahashi, M., Nakashima, I.: "Molecular mechanism of activation and superactivation of Ret tyrosine kinases by ultraviolet light irradiation"Antiox. Redox. Signal.. 2. 841-849 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kato, M., Iwashita, T., Takeda, K., Akhand, A.A., Liu, W., Yoshihara, M., Asai, N., Suzuki, H., Takahashi, M., Nakashima, I.: "Ultraviolet inudces redox reaction-mediated dimerization and superactivation of oncogenic Ret tyrosine kinases"Mol. Biol. Cell. 11. 93-101 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Dai Y, Kato M, Takeda K, Kawamoto Y, Akhand AA, Hossain K, Suzuki H, Nakashima I.: "T-cellimmunity-based inhibitory effects of orally administered herbal medicine juzen-taiho-to on the growth of primarily developed melanocytic tumors in RET-transgenic mice"J Invest Dermatol.. 117. 694-701 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kato, M, Takeda, K., Kawamoto, Y., Iwashita, T., Akhand. A.A., Senga, T., Yamamoto, M., Sobue, G., Hamaguchi, M., Takahashi, M., Nakashima, J.: "Repair by Src Kinase of Function-Impaired RET-MEN2A with Mutations at Tyrosines in the Carboxyterminal Kinase Domain"Cancer Res. in press.

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kato, M., Takeda, K., Kawamoto, Y., Tsuzuki, T., Dai, Y., Nakayama, S., Toriyama, K., Tamada, Y., Takahashi, M., Nakashima, I.: "RET tyrosine kinase enhances hair growth in association with promotion of melanogenesis"Qncogene. 20. 7536-7541 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshikawa, T. (Editor): "Oxidative stress - Recent advances in free radical biology and medicine"1-326 (2001)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2003-09-17  

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