2001 Fiscal Year Final Research Report Summary
Analysis of the mechanism of ultraviolet irradiation-mediated induction skin malignant melanoma
| Project/Area Number |
12670816
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Dermatology
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| Research Institution | Nagoya University |
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Principal Investigator |
NAKASHIMA Izumi Graduate School of Medicine, Nagoya University Professor, 大学院・医学研究科, 教授 (40022826)
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| 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)
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| Project Period (FY) |
2000 – 2001
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| Keywords | RET oncogene / RET-transgenic mice / ultraviolet / malignant / malignant melanoma / melanocytic tumors / oxidative stress / anti-oxidants |
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| 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.
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[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
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[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)
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「研究成果報告書概要(欧文)」より
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[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)
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「研究成果報告書概要(欧文)」より
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[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.
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「研究成果報告書概要(欧文)」より
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[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)
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「研究成果報告書概要(欧文)」より
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