B細胞の活性化と細胞死を制御する新規遺伝子のin vivoにおける機能

• 研究課題/領域番号: 13670328
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 免疫学
• 研究機関: 千葉県がんセンター(研究所)
• 研究代表者: 王 継揚 千葉県がんセンター, 病理研究部, 研究員 (80231041)
• 研究分担者: 田川 雅敏 千葉県がんセンター, 病理研究部, 部長 (20171572)
• 研究期間 (年度): 2001 – 2002
• 研究課題ステータス: 完了 (2002年度)
• 配分額: 3,500千円 (直接経費: 3,500千円); 2002年度: 1,300千円 (直接経費: 1,300千円); 2001年度: 2,200千円 (直接経費: 2,200千円)
• キーワード: リンパ球 / 増殖 / 遺伝子発現 / 免疫応答 / 転写因子 / CD40 / B細胞抗原レセプター / 免疫学 / 遺伝子 / アポトーシス / シグナル伝達

研究概要

B細胞の活性化を制御する分子機構を明らかにするために、私たちは休止期B細胞が活性化される際に発現誘導される遺伝子Clast1と、逆に活性化に伴い発現が抑制される遺伝子Clast5のin vivoにおける機能の解析を行った。Clast1分子をB細胞で特異的に発現させたトランスジェニック(Tg)マウスでは、抗原刺激に対するB細胞の反応性が上昇し、T依存性抗体産生が顕著に元進した。僅か一回の免疫で長期にわたり、抗原特異的なIgM抗体の産生が増加し続けた。これらの結果から、Clast1は、CD40からのシグナルによって特異的に誘導され、B細胞の活性化を正に制御する分子と推察された。一方、Clast5-Tgマウスにおいては、脾臓と胸腺の大きさ及び細胞数がコントロールの半分以下に減少した。また、抗IgM抗体やCD40リガンドなどの刺激に対し、B細胞の反応性が低下したことが示された。さらにT依存性抗原に対する抗体産生が障害され、胚中心の表現型をもつB細胞が減少した。従って、Clast5は、抗原レセプターをはじめ、様々な補助刺激分子からのシグナルの核内ターゲットであり、B細胞の活性化を負に制御する転写因子であることが示唆された。現在、ノックアウトマウスを作製中である。

研究成果

• [文献書誌] Tada, Y., O-Wang, J.et al.: "T cell-dependent antitumor effects produced by CD40 ligand expressed on mouse lung carcinoma cells are linked with the maturation of dendritic cells and secretion of a variety of cytokines"Cancer Gene Ther.. (in press).
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Mitsui, T., O-Wang, J.et al.: "Hypertension and angiotensin II hypersensitivity in aminopeptidase A-deficient mice"Mol.Med. 9. 57-62 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Tada, Y., O-Wang, J.et al.: "Fas ligand-expressing tumors induce tumor-specific protective immunity in the inoculated hosts but vaccination with the apoptotic tumors suppresses antitumor immunity"Cancer Gene Ther.. 10. 134-140 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Seimiya, M., O-Wang, J.et al.: "Stage-specific expression of Clast6/E3/LAPTM5 during B cell differentiation : ubiquitous expression in human B lymphomas"Int.J.Oncol.. 22. 301-304 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Tada, Y., O-Wang, J.et al.: "A novel role for Fas ligand in facilitating antigen acquisition by dendritic cells"J.Immunal.. 169. 2241-2245 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Bahar, R., O-Wang, J.et al.: "Growth retardation, polyploidy and multinucleation induced by Clast3, a novel cell cycle-regulated protein"J.Biol.Chem... 277. 40012-40019 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] O-Wang, J., Kajiwara, K., et al.: "An essential role for REV3 in memmalian cell survival : absence of REV3 induces p53-independent embryonic death"Biochem.Biophys.Res.Commun.. 293. 1132-1137 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Tada, Y., O-Wang, J.et al.: "Antitumor effects are produced by forced expression of membrane-bound by not soluble Fas ligand murine lung carcinoma cells"Anticancer.Res.. 22. 831-836 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Seimuya, M., O-Wang, J.et al.: "Clast5/Stra13 is a negative regulator of B lymphocyte activation"biochem.Biophys.Res.Commun.. 292. 121-127 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Tada, Y., O-Wang, J.et al.: "Expression of the TNF-(alpha) gene on mouse lung carcinoma cells suppresses spontaneous lung metastasis without affecting tumorigenicity"Oncology Report. 9. 585-588 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Tada, Y., O-Wang, J.et al.: "T cell dependent and independent antitumor immunity generated by the expression of Fas ligand on mouse lung carcinoma cells"Int.J.Mol.Med.. 9. 281-285 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Kawamura, K., O-Wang, J.et al.: "The error-prone DNA polymerase ζ catalytic subunit (Rev3) gene is ubiquitously expressed in normal and malignant human tissues"Int.J.Oncology. 18. 97-103 (2001)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Kajiwara, K., O-Wang, J.et al.: "Sez4 gene encoding an elongation subunit of DNA polymerase ζ is required for normal embryogenesis"Genes to Cells. 6. 99-106 (2001)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] O-Wang, J., Kawamura, K., et al.: "DNA polymerase κ, implicated in spontaneous and DNA damage-induced mutagenesis, is overexpressed in lung cancer"Cancer Res.. 61. 5366-5369 (2001)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Maeda, T., O-Wang, J.et al.: "A minimum c-erbB-2 promoter-mediated expression of herpes simplex virus-thymidine kinase gene confers selective cyto xicity of human breast cancer cells to ganiciclovir"Cancer Gene Ther.. 8. 890-896 (2001)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] O-Wang, J., Watanabe, T.: "Antigen Presentation to lymphocytes"Nature Publishing Group. 5 (2001)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Tada, Y., O-Wang, J. et al.: "T cell-dependent antitumor effects produced by CD40 ligand expressed on mouse lung carcinoma cells are linked with the maturation of dendritic cells and secretion of a variety of cytokines"Cancer Gene Ther.. in press.
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Mitsui, T., Nomura, S., Okada, M., Ohno, Y., Kobayashi, H., Nakashima, Y., Murata, Y., Takeuchi, M., Kuno, N., Nagasaka, T., O-Wang, J., D Cooper, M. and Mizutani, S: "Hypertension and angiotensin II hypersensitivity in aminopeptidase A-deficient mice"Mol. Med. 9. 57-62 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tada, Y., O-Wang, J., Wada, A., Takiguchi, Y., Tatsumi, K., Kuriyama, T., Sakiyama, S., Tagawa, M.: "Fas ligand-expressing tumors induce tumor-specific protective immunity in the inoculated hosts but vaccination with the apoptotic tumors suppresses antitumor immunity"Cancer Gene Ther.. 10. 134-140 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Seimiya, M., O-Wang, J., Bahar, R.. Kawamura, K., Wang, Y., Saisho, H., Tagawa, M.: "Stage-specific expression of Clast6/E3/LAPTM5 during B cell differentiation : ubiquitous expression in human B lymphomas"Int. J. Oncol.. 22. 301-304 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tada, Y., O-Wang, J., Takiguchi, Y., Tatsumi, K,Kuriyama, T., Okada, S., Tokuhisa, T.5 Sakiyama,S., Tagawa, M.: "A novel role for Fas ligand in facilitating antigen acquisition by dendritic cells"J. Immunal. 169. 2241-2245 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Bahar, R., O-Wang, J., Kawamura, K., Seimiya, M., Wang, Y., Hatano, M, Okada, S., Tokuhisa, T., Watanabe , T. and Tagawa, M.: "Growth retardation , polyploidy and multinucleation induced by Clast3, a novel cell cycle-regulate d protein"J. Biol. Chem.. 277. 40012-40019 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] O-Wang, J., Kajiwara, K., Kawamura, K., Kimura, M., Miyagishima, H., Koseki, H., Tagawa, M.: "An essential role for REV3 in mammalian cell survival : absence of REV3 induces p53-independent embryonic death"Biochem. Biophys. Res. Commun.. 293. 1132-1137 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tada, Y., O-Wang, J., Seimiya, M., Takiguchi, Y,Tatsumi, K., Kuriyama, T., Tagawa, M.: "Antitumor effects are produced by forced expression of membrane-bound by not soluble Fas ligand in murine lung carcinoma cells"Anticancer. Res.. 22. 831-836 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Seimiya, M., Bahar, R., Wang, Y., Kawamura, K., Tada, Y., Okada, S., Hatano, M., Tokuhisa, T., Saisho, H., Watanabe, T., Tagawa, M., O-Wang, J.: "Clast5/Stra13 is a negative regulator of B lymphocyte activation"Biochem. Biophys. Res. Commun.. 292. 121-127 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tada, Y., O-Wang, J., Takenaga, K., Takiguchi, Y., Tatsumi, K., Kuriyama, T., Tagawa, M.: "Expression of the TNF-α (alpha) gene on mouse lung carcinoma cells suppresses spontaneous lung metastasiswithout affecting tumorigenicity"Oncology Report. 9. 585-588 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tada, Y., O-Wang, J., Takiguchi, Y., Tatsumi, K., Kuriyama, T., Tagawa, M.: "T cell dependent and independent antitumor immunity generated by the expression of Fas ligand on mouse lung carcinoma cells"Int. J. Mol. Med.. 9. 281-285 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Kawamura, K., O-Wang, J., Bahar, R., Koshikawa, N., Shishikura, T., Nakagawara, A., Sakiyama, S., Kajiwara, K., Kimura, M., Tagawa, M.: "The error-prone DNA polymerase ζ catalytic subunit (Rev3) gene is ubiquitously expressed in normal and malignant human tissues"Int. J. Oncology. 18. 97-103 (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Kajiwara, K., O-Wang, J., Sakurai, T., Yamashita, S., Tanaka, M., Sato, M., Tagawa, M., Sugaya, E., Nakamura, K., Nakao, K., Katsuki, M., Kimura, M.: "Sez4 gene encoding an elongation subunit of DNA polymerase ζ is required for normal embryogenesis"Genes to Cells. 6. 99-106 (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] O-Wang, J., Kawamura, K., Tada, Y., Ohmori, H., Kimura, H., Sakiyama, S., Tagawa, M.: "DNA polymerase κ, implicated in spontaneous and DNA damage-induced mutagenesis, is overexpressed in lung cancer"Cancer Res.. 61. 5366-5369 (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Maeda, T., O-Wang, J. Matsubara, H., Asano, A., Ochiai, T., Sakiyama, S. and Tagawa, M.: "A minimum c-erbB-2 promoter-mediated expression of herpes simplex virus-thymidine kinase gene confers selective cytotoxicity of human breast cancer cells to ganciclovir"Cancer Gene Ther.. 8. 890-896 (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Jiyang O-Wang, Takeshi Watanabe: "Antigen presentation to Lymphocytes"Neture Publishing Group. 5 (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Mitsui, T., O-Wang, J.et al.: "Hypertension and angiotensin II hypersensitivity in aminopeptidase A-deficient mice"Mol. Med. (in press).
• [文献書誌] Tada, Y., O-Wang, J.et al.: "T cell-dependent antitumor effects produced by CD4O ligand expressed on mouse lung carcinoma cells are linked with the maturation of dendritic cells and secretion of a variety of cytokines"Cancer Gene Ther.. (in press).
• [文献書誌] Tada, Y., O-Wang, J.et al.: "Fas ligand-expressing tumors induce tumor-specific protective immunity in the inoculated hosts but vaccination with the apoptotic tumors suppresses antitumor immunity"Cancer Gene Ther.. (in press).
• [文献書誌] Seimuya, M., O-Wang, J.et al.: "Stage-specific expression of Clast6/E3/LAPTM5 during B cell differentiation : ubiquitous expression in human B lymphomas"Int. J. Oncol.. 22. 301-304 (2003)
• [文献書誌] Tada, Y., O-Wang, J.et al.: "A novel role for Fas ligand in facilitating antigen acquisition by dendritic cells"J. Immunal.. 169. 2241-2245 (2002)
• [文献書誌] Bahar, R., O-Wang, J.et al.: "Growth retardation, polyploidy and multinucleation induced by Clast3, a novel cell cycle-regulated protein"J. Biol. Chem.. 277. 40012-40019 (2002)
• [文献書誌] O-Wang, J., Kajiwara, K.et al.: "An essential role for REV3 in mammalian cell survival : absence of REV3 induces p53-independent embryonic death"Biochem. Biophys. Res. Commun.. 293. 1132-1137 (2002)
• [文献書誌] Tada, Y., O-Wang, J.et al.: "Antitumor effects are produced by forced expression of membrane-bound by not soluble Fas ligand in murine lung carcinoma cells"Anticancer. Res.. 22. 831-836 (2002)
• [文献書誌] Seimuya, M., O-Wang, J.et al.: "Clast5/Stra13 is a negative regulator of B lymphocyte activation"Biochem. Biophys. Res. Commun.. 292. 121-127 (2002)
• [文献書誌] Tada, Y., O-Wang, J.et al.: "Expression of the TNF-_(alpha) gene on mouse lung carcinoma cells suppresses spontaneous lung metastasis without affecting tumorigenicity"Oncology Report. 9. 585-588 (2002)
• [文献書誌] Tada, Y., O-Wang, J.et al.: "T cell dependent and independent antitumor immunity generated by the expression of Fas ligand on mouse lung carcinoma cells"Int. J. Mol. Med.. 9. 281-285 (2002)
• [文献書誌] Kawamura, K., O-Wang, J.et al.: "The error-prone DNA polymerase ζ catalytic subunit(Rev3)gene is ubiquitously expressed in normal and malignant human tissues"Int. J. Oncology. 18. 97-103 (2001)
• [文献書誌] Kawamura, K., O-Wang, J.et al.: "Sez4 gene encoding an elongation subunit of DNA polymerase ζ is required for normal embryogenesis"Genes to Cells. 6. 99-106 (2001)
• [文献書誌] O-Wang, J.Kawarnura, K., et al.: "DNA polymerase κ, implicated in spontaneous and DNA damage-induced mutagenesis, is overexpressed in lung cancer"Cancer Red.. 61. 5366-5369 (2001)
• [文献書誌] Maeda, T., O-Wang, J.et al.: "A minimum c-erbB-2 promoter-mediated expression of herpes simplex virus-thymidine kinase gene confers selective cytotoxicity of human breast cancer cells to ganciclovir"Cancer Gene Ther.. (in press). (2002)
• [文献書誌] Tada, Y., O-Wang, J.et al.: "Antitumor effects are produced by forced expression of membrane-bound by not soluble Fas ligand in murine lung carcinoma cells"Anticancer Res.. (in press). (2002)
• [文献書誌] Tada, Y., O-Wang, J.et al.: "T cell dependent and independent antitumor immunity generated by the expression of Fas ligand on mouse lung carcinoma cells"Int. J. Mol. Mod.. (in press). (2002)