高発がん性ラットを用いた発がん過程の主要因の解析

• 研究課題/領域番号: 08264108
• 研究種目: 重点領域研究
• 配分区分: 補助金
• 研究機関: (財)癌研究会
• 研究代表者: 樋野 興夫 (財)癌研究会, 癌研究所・実験病理部, 部長 (90127910)
• 研究分担者: 小林 敏之 (財)癌研究会, 癌研究所・実験病理部, 研究員 (40260070) ; 小西 陽一 奈良県立医科大学, 教授 (00075061) ; 松山 睦司 藤田保健衛生大学, 医学部, 教授 (80073112) ; 白井 智之 名古屋市立大学, 医学部, 教授 (60080066) ; 榎本 克彦 秋田大学, 医学部, 教授 (20151988) ; 芹川 忠夫 京都大学, 医学部, 教授 (30025655)
• 研究期間 (年度): 1999 – 2000
• 研究課題ステータス: 完了 (2000年度)
• 配分額: 107,000千円 (直接経費: 107,000千円); 1999年度: 5,000千円 (直接経費: 5,000千円); 1998年度: 33,000千円 (直接経費: 33,000千円); 1997年度: 33,000千円 (直接経費: 33,000千円); 1996年度: 36,000千円 (直接経費: 36,000千円)
• キーワード: Ekerラット / 疾患モデル / 遺伝性腎がん / TSC2遺伝子 / 結節性硬化症 / がん抑制遺伝子 / 多段階発がん / 遺伝性癌 / 癌感受性遺伝子 / LECラット / BUM / Mnaラット / ラットゲノム / BUF / ラット発癌 / 腎癌 / 肝癌 / 前立腺癌 / 胸腺腫 / wilms腫瘍 / Canier Genetics

研究概要

ヒト多段階発がんの理解は、(1)がん進展阻止、(2)がん制御につながり、がん研究のバックボーンであると考える(Molecular Medicine 36:348-357,1999)。ヒトを対象としては不可能であることを、リファインされた疾患モデルを用いてヒト多段階がん化機構解明およびがんの治療に資することは極めて重要である。本研究では、起始遺伝子(Tsc2)に変異を持つ、疾患モデルを用い、ヒト多段階発がんの理解に貢献しようとするものである。本年度以下の点を明らかにした。
1.変異型Tsc2遺伝子を導入したTransgenic Eker ratの作製と解析を行った。
2.Tsc2遺伝子knockoutマウスによるTsc2遺伝子の腎がん遺伝子の証明を行った。
3.Tsc2遺伝子knockoutマウスと他の遺伝子操作マウスとの交配実験を行った。
4.Tsc2がん抑制遺伝子の発現制御機構の解明を行った。
5.多段階発がん過程で特異的に発現してくる新規遺伝子を単離した。

研究成果

• [文献書誌] Satake,N.: "Isolation and characterization of a rat homologue of the human tuberous sclerosis 1 gene (TSC1) and analysis..."Cancer Res. 59. 849-855 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Kobayashi,T.: "Renal carcinogenesis, hepatic hemangiomatosis and embryonic lathality caused by a germiline TSC2..."Cancer Res.. 59. 1206-1211 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Fukuda,T.: "Distribution of TSC2 protein in various normal rat tissues and renal tumors of TSC2 mutant (Eker) rat..."Virchows.Archiv. 434. 341-350 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Fukuda,T: "Cloning of differentially expressed genes in highly and low metastatic rat osteosaroomas by a modified"Biochem.Biophys.Res.Commun. 261. 35-40 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Yamashita,Y.: "Analysis of the entire TSC1 and TSC2 gene for germline mutations in Japanese cases of Tuberous"Am.J.Med.Genet. 90. 123-126 (2000)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Mizuguchi,M,: "Novel cerebral lesions in the Eker rat model of tuberous sclerosis, Cortical tuber and ansplastic..."J.Neuropathol.Exp.Neurol. (in press). (2000)
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• [文献書誌] Satake, N., Kobayashi, T., Kobayashi, E,, Izumi, K.and Hino, O.: "Isolation and characterization of a rat homologue of the human tuberous sclerosis 1 gene (TSC 1) and analysis of its mutations in rat renal carcinomas."Cancer Res.. 59. 849-855 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Kobayashi, T., Minow, O., Kuno, J., Mitani, H.Hino O.and Noda T: "Renal carcinogenesis, hepatic hemangiomatosis and embryonic lethality caused by a germline Tsc 2 mutation in mice."Cancer Res.. 59. 1206-1211 (1999)
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• [文献書誌] Hino, O., Fukuda, T., Satake, N., Kobayashi, T., Honda, S., Orimoto, K., Yamashita, Y.and Kikuchi, Y.: "TSC2 gene mutant (Eker) rat model of a mendelian dominantly inherited cancer."Prog.Exp.Tumor Res.(Eds.Hiai, H.and Hino, O,), Karger, Basel. 35. 95-108 (1999)
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• [文献書誌] Fukuda, T., Kobayashi, T., Yasui, H., Tsutsumi, M., Konishi, Y.and Hino, O.: "Distribution of Tsc2 protein in various normal rat tissues and renal tumors of Tsc2 mutant (Eker) rat detected by immunohistochemistry"Virchows Archiv. 434. 341-350 (1999)
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• [文献書誌] Kajino, K.and Hino, O.: "TSC 1 and TSC 2 genes mutations in Human Kidney tumors. "Kidney Cancer" (Recent Results of Basic and Clinical Research) In Contibution to Nephrology (Ed.Hino, O.)"Karger, Basel. 128. 45-50 (1999)
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• [文献書誌] Fukuda, T., Kido, A., Kajino, K., Tsutsumi, M., Miyauchi, Y., Tsujiuchi, T., Konishi, Y.and Hino, O.: "Cloning of differentially expressed genes in highly and low metastatic rat osteosarcomas by a modified cDNA-AFLP method"Biochem.Biophys.Res.Commun.. 261. 35-40 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Yamashita, Y., Ono, J., Okada, S., Wataya-Kaneda, M., Yoshikawa, K., Nishizawa, M., Hirayama, Y., Kobayashi, E., Seyama, K.and Hino, O.: "Analysis of the entire TSC1 and TSC2 genes for germline mutations in Japanese cases of tuberous sclerosis : Reports of ten mutations"Am.J.Med.Genet. 90. 123-126 (2000)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Mizuguch, M., Takashima, S., Yamanouch, H., Nakazato, Y., Mitani, H.and Hino, O.: "Novel cerebral lesions in the Eker rat model of tuberous sclerosis, Cortical tuber and anaplastic ganglioglioma"J.Neuropathol.Exp.Neurol.. (in press).
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• [文献書誌] Hino, O., Satake, N., Kobayashi, T.and Kajino, K.: "Carcinogenesis in tuberous sclerosis. Gann Monograph on Cancer Reserach No.46 : (Eds.Ohtuka, F., Hino, O.and Niimura, M.)"Japan Scientific Societies Press, Tokyo. 101-111 (1999)
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• [文献書誌] Hino, O., Kobayashi, T., Orimoto, K., Urakami, S., Fukuda, T., Satake, N.and Yamashita, Y.: "Cancer genetics of the tuberous sclerosis (TSC2) gene mutant. Familal Cancer and Prevention (Eds.Utsunomiya, J., Mulvihill, J.J.and Weber, W.)"A Jone Wiley & Sons, Inc., New York. 475-480 (1999)
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• [文献書誌] Satake, N.: "Isolation and characterization of a rat homologue of the human tuberous sclerosis 1 gene (TSC1) and anaiysis of its mutations in rat renal carcinomas"Cancer Res.. 59. 849-855 (1999)
• [文献書誌] Kobayashi, T.: "Renal carcinogenesis, hepatic hemangiomatosis and embryonic lethallty cused by a germline Tsc2 mutation in mice"Cancer Res.. 59. 1206-1211 (1999)
• [文献書誌] Fukuda, T: "Distribution of Tsc2 protein in various normal rat tissues and renal tumours of Tsc2 mutant (Eker) rat detected by immunohistochemistry"Vischows. Archiv. 434. 341-350 (1999)
• [文献書誌] Fukuda, T.: "Cloning of differentially expressed genes in highly and low metastatic rat osteosarcomas by a modified cDNA-AFLP method"Biochem. Biophys. Res. Commun. 261. 35-40 (1999)
• [文献書誌] Yamashita, Y.: "Analysis of the entire TSC1 and TSC2 gene for germline mutation in Japanese cases of tuberous sclerosis : Reporrts of ten mutation"Am. J. Med. Genet.. 90. 123-126 (2000)
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