1995 年度実績報告書

β型トランスフォーミング増殖因子レセプターの作用の研究と臨床応用

研究課題

研究課題/領域番号	07557334
研究種目	試験研究(B)
研究機関	(財)癌研究会
研究代表者	宮園浩平財団法人癌研究會, 癌研究所生化学部, 部長 (90209908)
研究分担者	加藤光保財団法人癌研究會, 癌研究所・生化学部, 研究員 (20194855) 一條秀憲財団法人癌研究會, 癌研究所・生化学部, 研究員 (00242206) 川畑正博財団法人癌研究會, 癌研究所・生化学部, 研究員 (60224838)
キーワード	TGF-β / レセプター / 癌抑制遺伝子 / シグナル伝達 / 免疫抑制剤 / cDNAクローニング / 増殖抑制 / セリン-スレオニンキナーゼ
研究概要	1.β型トランスフォーミング増殖因子(TGF-β)レセプターの種々の疾患における発現:TGF-βのI型、II型レセプターの発現を検討し、胃癌や脳腫瘍などの組織では悪性度が増すにつれてレセプターの発現が上昇することを確認した。一方、分子レベルでは遺伝性大腸癌でII型レセプターに変異がみられることが報告され、我々はさまざまな扁平上皮癌でII型レセプターの遺伝子異常の有無を現在検討中である。これに対し、前立腺癌の細胞株LNCaPではI型レセプターに異常があることを確認した。 2.TGF-βレセプターに対するTGF-βの結合部位の研究:TGF-βIII型レセプターに対する結合部位にはN末端近傍とC末端近傍に2カ所のリガンド結合部位があることを確認した。現在その機能的役割を検討中で、今後新しい薬剤をデザインするさいの貴重な情報となると考えられる。 3.TGF-βII型レセプターによるI型レセプターの活性化のメカニズムの研究:TGF-βのI型レセプター活性化にはGSドメインとよばれる特異的構造が重要であることが知られている。今回我々は、I型レセプターの膜貫通領域とGSドメインの間に位置する領域に変異を加えることによってこの領域が細胞増殖抑制のシグナル伝達には重要であるが、細胞外マトリックスの産生は重要ではないことを示唆する所見を得た。 4.TGF-βレセプターの細胞内基質の同定とcDNAクローニング:我々は酵母を用いたtwo-hybrid法によってFKBP-12(免疫抑制剤の結合タンパク質)とfarnesyl transferase-α(FT-α)がTGF-βのI型レセプターと結合することを見いだした。またFKBP-12とFT-αは酵母のシステムだけでなくヒトの培養細胞内でも結合することを確認した。

研究成果
(17件)

すべてその他

すべて文献書誌 (17件)

[文献書誌] ten Dijke,P.: "Signaling via hetero-oligomeric complexes of type I and type II serine/threonine kinase receptors" Current Opinion in Cell Biology. (in press). (1996)
[文献書誌] Miyazono,K.: "TGF-β receptors and signal transduction" Proceedings of International Symposium on Bone Marrow Transplantation. (in press). 1996
[文献書誌] Yamada,N.: "Enhanced expression of transforming growth factor-β and its type-I and type-II receptors in human glioblastoma" International Journal of Cancer. 62. 386-392 (1995)
[文献書誌] Henriksen,R.: "Expression and prognostic significance of TGF-β isotypes, latent TGF-β1 binding protein, TGF-β type I and type II receptors, and endoglin in normal ovary and ovarian neoplasms" Laboratory Investigation. 73. 213-220 (1995)
[文献書誌] Kim,I.Y.: "Genetic change in transforming growth factor-β (TGF-β) receptor type I gene correlates with insensitivity to TGF-β1 in human prostatic cancer cells" Cancer Resear ch. 56. 44-48 (1996)
[文献書誌] Kai,T.: "Distribution of transforming growth factor-β and its receptors in gastric carcinoma tissue" Japanese Journal of Cancer Research. (in press). (1996)
[文献書誌] Yamada,N.: "Bone morphogenetic protein type IB receptor is progressively expressed in malignant glioma tissues" British Journal of Cancer. (in press). (1996)
[文献書誌] Kawabata,M.: "Interaction of the transforming growth factor-β type I receptor with farnesyl-protein transferase-alfa" Journal of Biological Chemistry. 270. 29628-29631 (1995)
[文献書誌] Tamaki,K.: "Matrix-associated latent TGF-β with latent TGF-β binding protein in the progressive process in adriamycin-induced nephropathy" Laboratory Investigation. 73. (1995)
[文献書誌] Tamaki,K.: "Matrix-associated latent TGF-β with latent TGF-β binding protein in the progressive process in adriamycin-induced nephropathy" Laboratory Investigation. 73. (1995)81-89
[文献書誌] Van Laethem,J.-L.: "Localization of transforming growth factor β1 precursor and latent TGF-β1 binding protein in human chronic pancreatitis" Gastroenterology. 108. 1873-1881 (1995)
[文献書誌] Chen,R.-H.: "Phosphorylation-dependent interaction of the cytoplasmic domains of the type I and type II transforming growth factor-β receptors" Journal of Biological Chemistry. 270. 12235-12241 (1995)
[文献書誌] Saitoh,M.: "Identification of important regions in the cytoplasmic juxtamembrane domain of type I receptor that separate signaling pathways of transforming growth factor-β" Journal of Biological Chemistry. 271. 2769-2775 (1996)
[文献書誌] Iseki,S.: "Localization of transforming growth factor-β type I and type II receptors in mouse development" Experimental Cell Research. 219. 339-347 (1995)
[文献書誌] Yamashita,H.: "Osteogenic protein-1 binds to activin type II receptors and induces certain activin-like effects" Journal of Cell Biology. 130. 217-226 (1995)
[文献書誌] Rosenzweig,B.L.: "Cloning and characterization of a human type II receptor for bone morphogenetic proteins" Proceedings of the National Academy of Sciences of USA. 92. 7632-7636 (1995)
[文献書誌] de Vries,C.J.M.: "Active complex formation of type I and type II activin and TGFβ receptors in vivo as studied by overexpression in zebrafish embryos" Mechanisms of Development. 54. 225-236 (1996)

1995 年度 実績報告書

β型トランスフォーミング増殖因子レセプターの作用の研究と臨床応用

研究代表者

宮園 浩平 財団法人癌研究會, 癌研究所生化学部, 部長 (90209908)

研究成果

[文献書誌] ten Dijke,P.: "Signaling via hetero-oligomeric complexes of type I and type II serine/threonine kinase receptors" Current Opinion in Cell Biology. (in press). (1996)

[文献書誌] Miyazono,K.: "TGF-β receptors and signal transduction" Proceedings of International Symposium on Bone Marrow Transplantation. (in press). 1996

[文献書誌] Yamada,N.: "Enhanced expression of transforming growth factor-β and its type-I and type-II receptors in human glioblastoma" International Journal of Cancer. 62. 386-392 (1995)

[文献書誌] Henriksen,R.: "Expression and prognostic significance of TGF-β isotypes, latent TGF-β1 binding protein, TGF-β type I and type II receptors, and endoglin in normal ovary and ovarian neoplasms" Laboratory Investigation. 73. 213-220 (1995)

[文献書誌] Kim,I.Y.: "Genetic change in transforming growth factor-β (TGF-β) receptor type I gene correlates with insensitivity to TGF-β1 in human prostatic cancer cells" Cancer Resear ch. 56. 44-48 (1996)

[文献書誌] Kai,T.: "Distribution of transforming growth factor-β and its receptors in gastric carcinoma tissue" Japanese Journal of Cancer Research. (in press). (1996)

[文献書誌] Yamada,N.: "Bone morphogenetic protein type IB receptor is progressively expressed in malignant glioma tissues" British Journal of Cancer. (in press). (1996)

[文献書誌] Kawabata,M.: "Interaction of the transforming growth factor-β type I receptor with farnesyl-protein transferase-alfa" Journal of Biological Chemistry. 270. 29628-29631 (1995)

[文献書誌] Tamaki,K.: "Matrix-associated latent TGF-β with latent TGF-β binding protein in the progressive process in adriamycin-induced nephropathy" Laboratory Investigation. 73. (1995)

[文献書誌] Tamaki,K.: "Matrix-associated latent TGF-β with latent TGF-β binding protein in the progressive process in adriamycin-induced nephropathy" Laboratory Investigation. 73. (1995)81-89

[文献書誌] Van Laethem,J.-L.: "Localization of transforming growth factor β1 precursor and latent TGF-β1 binding protein in human chronic pancreatitis" Gastroenterology. 108. 1873-1881 (1995)

[文献書誌] Chen,R.-H.: "Phosphorylation-dependent interaction of the cytoplasmic domains of the type I and type II transforming growth factor-β receptors" Journal of Biological Chemistry. 270. 12235-12241 (1995)

[文献書誌] Saitoh,M.: "Identification of important regions in the cytoplasmic juxtamembrane domain of type I receptor that separate signaling pathways of transforming growth factor-β" Journal of Biological Chemistry. 271. 2769-2775 (1996)

[文献書誌] Iseki,S.: "Localization of transforming growth factor-β type I and type II receptors in mouse development" Experimental Cell Research. 219. 339-347 (1995)

[文献書誌] Yamashita,H.: "Osteogenic protein-1 binds to activin type II receptors and induces certain activin-like effects" Journal of Cell Biology. 130. 217-226 (1995)

[文献書誌] Rosenzweig,B.L.: "Cloning and characterization of a human type II receptor for bone morphogenetic proteins" Proceedings of the National Academy of Sciences of USA. 92. 7632-7636 (1995)

[文献書誌] de Vries,C.J.M.: "Active complex formation of type I and type II activin and TGFβ receptors in vivo as studied by overexpression in zebrafish embryos" Mechanisms of Development. 54. 225-236 (1996)

1995 年度実績報告書

宮園浩平財団法人癌研究會, 癌研究所生化学部, 部長 (90209908)