1995 年度実績報告書

インジュリン/HGFシステムによる器官再生並びに器官恒常性維持の分子機構

研究課題

研究課題/領域番号	05404080
研究機関	大阪大学
研究代表者	中村敏一大阪大学, 医学部, 教授 (00049397)
研究分担者	小清水右一大阪大学, 医学部, 助手根本康夫大阪大学, 医学部, 助手 (30250088) 松本邦夫大阪大学, 医学部, 講師 (90201780)
キーワード	HGF / インジュリン / c-met / 器官再生 / IL-1 / カルシノーマ / 器官形成
研究概要	HGFは上皮-間葉相互作用のメディエーターとして器官や組織の形成や再生に重要な役割を担っていることをこれまで肝臓や腎臓の形成や再生を対象に明らかにしてきた。本年度は肺や歯の発生におけるHGFの機能についてin situハイブリダイゼーション法やアンチセンスオリゴヌクレオチドを用いた解析を行った。ラット胎児肺においては活発に枝分れを繰り返す気管支上皮組織においてc-met/HGFレセプターが、他方HGFはその周辺の間葉組織で発現することが明らかになった。さらに器官培養系においてリコンビナントHGFは肺原基の枝分れ(branching morphogenesis)促進する一方、HGFのアンチセンスオリゴDNAを添加して内因性HGF産生を抑制すると肺原基の枝分れが著しく阻害された。また、歯胚形成においてもHGFは歯胚間葉組織に、そのレセプターは上皮であるエナメル芽細胞に発現しており、やはりこの正常な歯の発生もHGFのアンチセンスオリゴDNA添加により上皮間葉相互作用をブロックすると著しく阻害された。乳腺の発生においても同様な結果が得られており、HGFは様々な上皮系組織の形態形成因子であることが明らかになった。一方、未知のインジュリンを発見する目的で約50種類にのぼるカルシノーマの細胞培養を行い、その培養上清中のHGF誘導活性(インジュリン活性)をヒト皮膚線維芽細胞を用いて測定した。その結果、調べた約50%のカルシノーマがインジュリン様因子を産生していることが明らかになった。それらの因子を同定したところ、大部分はIL-1,EGF,PDGF,bFGFなどの既知サイトカインであったが、マウス乳がん細胞(MMT)の産生するインジュリンはいずれの既知因子とも該当しなかった。このMMT細胞が産生するインジュリンは分子量約800で、熱及び酸処理に安定な因子であり、現在単一標品にまで精製中である。

研究成果

(35件)

すべてその他

すべて文献書誌 (35件)

[文献書誌] N.Nakayama: "Differing distribution of hepatocyte growth factor-positive cells in the liver of LEC rats with acute hepatitis, chronic hepatitis and hepatoma." Jap. J. Cancer Res.86. 5-9 (1995)
[文献書誌] H.Nakamura: "Molecular cloning of Xenopus HGF cDNA, and its expression studied in Xenopus early embryogenesis." Mech. Develop.49. 121-131 (1995)
[文献書誌] G.Shiota: "Serum hepatocyte growth factor level: its clinical implication." Hepatology. 21. 106-112 (1995)
[文献書誌] W.G.Jiang: "Inhibition of motility and invasion by invasion inhibiting factor-2(11F-2)on human colon cancer cells." Surg. Res. Commun.17. 67-78 (1995)
[文献書誌] K.Matsumoto: "Novel function of prostaglandins as inducer of gene expression of hepatocyte growth factor." J. Biochem.117. 458-464 (1995)
[文献書誌] F.Myokai: "Expression of the hepatocyte growth factor gene during development of the chicken limb." Develop. dynamics. 202. 80-90 (1995)
[文献書誌] T.Sato: "Hepatocyte growth factor(HGF)is involved in the formation of osteoclast-like cells mediated by clonal stromal cells(MC3T3-G1/PA6)." J. Cell. Physiol.164. 197-204 (1995)
[文献書誌] M.J.Gomez-Lechon: "Effect of hepatocyte growth factor(h-rHGF)on the growth and metabolism of human hepatocytes in primary culture." Hepatology. 21. 1248-1254 (1995)
[文献書誌] S.Saito: "Hepatocyte growth factor promotes the growth of cytotrophoblasts by the paracrine system." J.Biochem.117. 671-676 (1995)
[文献書誌] M.Takahashi: "Hepatocyte growth factor is the most potent endogenous stimulant of rabbit gastric epithelial cell proliferation and migration in primary culture." J. Clin. Invest.95. 1994-2003 (1995)
[文献書誌] T.Takabayashi: "Hepatocyte growth factor/scatter factor has mitogenic, motogenic and morphogenetic activities on chondrocytes." J. Cell Biol.129. 1411-1419 (1995)
[文献書誌] K.Matsumoto: "Hepatocyte growth factor as a potent survival factor for rat pheochromocytoma PC12 cells." Exp. Cell Res.220. 71-78 (1995)
[文献書誌] S.Seslar: "Tumor-stroma interactions and stromal cell density regulate hepatocyte growth factor protein levels: A role for transforming growth factor-b activation." Endocrinology. 136. 1945-1953 (1995)
[文献書誌] A.Yamada: "Rapid and sensitive enzyme-linked immunosorbent assay for measurement of HGF in rat and human tissues." Biomed. Res.16. 105-114 (1995)
[文献書誌] E.J.G.Barros: "Differential tubulogenic and branching morphogenetic activities of growth factors: Implications for epithelial tissue development." Proc. Natl. Acad. Sci.USA. 92. 4412-4416 (1995)
[文献書誌] H.Shimura: "Induction of invasive growth in a gallbladder cancer cell line by hepatocyte growth factor in vitro." Jap. J. Cancer Res.86. 662-669 (1995)
[文献書誌] K.Ohashi: "Molecular cloning, characterization and in situe localization in the brain of rat sky receptor tyrosine kinase." J. Biochem.117. 1267-1275 (1995)
[文献書誌] T.Adachi: "Roles of prostaglandin production and MAP kinase activation in hepatocyte growth factor-mediated rat hepatocyte proliferation." Hepatology. 21. 1668-1674 (1995)
[文献書誌] M.Yaono: "Hepatocyte growth factor enhancement of GST-P positive hepatic foci development in rats treated with diethylnitrosamine and N-ethyl-N-hydroxy ethylnitrosamine." Jap. J. Cancer Res.86. 718-723 (1995)
[文献書誌] W.G.Jiang: "Inhibition of HGF/SF-induced membrane ruffing and cell motility by transient elevation of cytosolic free Ca^<2+>." Exp. Cell Res.220. 424-433 (1995)
[文献書誌] Y.Matsuda: "Hepatocyte growth factor prevents liver cirrhosis caused by dimethylnitrosamine in rats." J. Biochem.118. 643-649 (1995)
[文献書誌] S.Honda: "Localization and functional coupling of HGF and c-Met/HGF receptor in rat brain: implication as neurotrophic factor." Mole. Brain Res.32. 197-210 (1995)
[文献書誌] M.R.Vila: "Hepatocyte growth factor is a potent mitogen for normal human pancreas cells in vitro." Lab. Invest.73. 409-418 (1995)
[文献書誌] P.Gines: "Tyrosine kinase growth factor receptors but not seven-membrane-spanning or phorbol esters activate mitogen-activated protein kinase in rat hepatocytes." Hepatology. 22. 1296-1303 (1995)
[文献書誌] M.Hu: "Human peri-tumoral and lung fibroblasts produce paracrine motility factors for recently established human sarcoma cell strains." Intn. J. Cancer. 62. 585-592 (1995)
[文献書誌] Y.Nakamura: "Expression of local hepatocyte growth factor system in vascular tissue." Biochem. Biophys. Res. Commun.215. 483-488 (1995)
[文献書誌] M.Takahashi: "Hepatocyte growth factor stimulates wound repair of the rabbit esophageal epithelial cells in primary culture." Biochem. Biophys. Res. Commun.216. 298-305 (1995)
[文献書誌] W.G.Jiang: "Induction of tyrosine phosphorylation and translocation of ezrin by hepatocyte growth factor/scatter factor(HGF/SF)." Biochem. Biophys. Res. Commun.217. 1062-1069 (1995)
[文献書誌] T.Kaido: "Continous HGF supply from spleen transplanted HGF-expressing fibroblasts prevents CCl_4-induced acute liver injury in rats." Biochem. Biophys. Res. Commun.218. 1-5 (1996)
[文献書誌] K.Matsumoto: "Hepatocyte growth factor as a renotropic factor and therapeutic potential for acute renal failure." Acute Renal Failure: Emerging New Concepts and Therapeutic Strategies., 24 (1995)
[文献書誌] H.Amaike: "Takahashi Memorial Forum, Tokyo, 5 November 1994,Excepta Medica International Congress Series 1086" Elsevier Science B. V. Amsterdam., 14 (1995)
[文献書誌] 坂倉照好: "細胞外マトリックス" 羊土社, 13 (1995)
[文献書誌] 中村敏一: "用語ライブラリー:発生・神経" 羊土社, 163 (1996)
[文献書誌] 中村敏一監訳: "細胞増殖因子(I. A. McKay and I. M. Leigh編)" メディカル・サイエンスインターナショナル, 232 (1995)
[文献書誌] U.Koshimizu: "Liver and Environmental Xenobiotics" Narosa-Elsevier Verlag(in press), (1996)

1995 年度 実績報告書

インジュリン/HGFシステムによる器官再生並びに器官恒常性維持の分子機構

研究代表者

中村 敏一 大阪大学, 医学部, 教授 (00049397)

研究成果

[文献書誌] N.Nakayama: "Differing distribution of hepatocyte growth factor-positive cells in the liver of LEC rats with acute hepatitis, chronic hepatitis and hepatoma." Jap. J. Cancer Res.86. 5-9 (1995)

[文献書誌] H.Nakamura: "Molecular cloning of Xenopus HGF cDNA, and its expression studied in Xenopus early embryogenesis." Mech. Develop.49. 121-131 (1995)

[文献書誌] G.Shiota: "Serum hepatocyte growth factor level: its clinical implication." Hepatology. 21. 106-112 (1995)

[文献書誌] W.G.Jiang: "Inhibition of motility and invasion by invasion inhibiting factor-2(11F-2)on human colon cancer cells." Surg. Res. Commun.17. 67-78 (1995)

[文献書誌] K.Matsumoto: "Novel function of prostaglandins as inducer of gene expression of hepatocyte growth factor." J. Biochem.117. 458-464 (1995)

[文献書誌] F.Myokai: "Expression of the hepatocyte growth factor gene during development of the chicken limb." Develop. dynamics. 202. 80-90 (1995)

[文献書誌] T.Sato: "Hepatocyte growth factor(HGF)is involved in the formation of osteoclast-like cells mediated by clonal stromal cells(MC3T3-G1/PA6)." J. Cell. Physiol.164. 197-204 (1995)

[文献書誌] M.J.Gomez-Lechon: "Effect of hepatocyte growth factor(h-rHGF)on the growth and metabolism of human hepatocytes in primary culture." Hepatology. 21. 1248-1254 (1995)

[文献書誌] S.Saito: "Hepatocyte growth factor promotes the growth of cytotrophoblasts by the paracrine system." J.Biochem.117. 671-676 (1995)

[文献書誌] M.Takahashi: "Hepatocyte growth factor is the most potent endogenous stimulant of rabbit gastric epithelial cell proliferation and migration in primary culture." J. Clin. Invest.95. 1994-2003 (1995)

[文献書誌] T.Takabayashi: "Hepatocyte growth factor/scatter factor has mitogenic, motogenic and morphogenetic activities on chondrocytes." J. Cell Biol.129. 1411-1419 (1995)

[文献書誌] K.Matsumoto: "Hepatocyte growth factor as a potent survival factor for rat pheochromocytoma PC12 cells." Exp. Cell Res.220. 71-78 (1995)

[文献書誌] S.Seslar: "Tumor-stroma interactions and stromal cell density regulate hepatocyte growth factor protein levels: A role for transforming growth factor-b activation." Endocrinology. 136. 1945-1953 (1995)

[文献書誌] A.Yamada: "Rapid and sensitive enzyme-linked immunosorbent assay for measurement of HGF in rat and human tissues." Biomed. Res.16. 105-114 (1995)

[文献書誌] E.J.G.Barros: "Differential tubulogenic and branching morphogenetic activities of growth factors: Implications for epithelial tissue development." Proc. Natl. Acad. Sci.USA. 92. 4412-4416 (1995)

[文献書誌] H.Shimura: "Induction of invasive growth in a gallbladder cancer cell line by hepatocyte growth factor in vitro." Jap. J. Cancer Res.86. 662-669 (1995)

[文献書誌] K.Ohashi: "Molecular cloning, characterization and in situe localization in the brain of rat sky receptor tyrosine kinase." J. Biochem.117. 1267-1275 (1995)

[文献書誌] T.Adachi: "Roles of prostaglandin production and MAP kinase activation in hepatocyte growth factor-mediated rat hepatocyte proliferation." Hepatology. 21. 1668-1674 (1995)

[文献書誌] M.Yaono: "Hepatocyte growth factor enhancement of GST-P positive hepatic foci development in rats treated with diethylnitrosamine and N-ethyl-N-hydroxy ethylnitrosamine." Jap. J. Cancer Res.86. 718-723 (1995)

[文献書誌] W.G.Jiang: "Inhibition of HGF/SF-induced membrane ruffing and cell motility by transient elevation of cytosolic free Ca^<2+>." Exp. Cell Res.220. 424-433 (1995)

[文献書誌] Y.Matsuda: "Hepatocyte growth factor prevents liver cirrhosis caused by dimethylnitrosamine in rats." J. Biochem.118. 643-649 (1995)

[文献書誌] S.Honda: "Localization and functional coupling of HGF and c-Met/HGF receptor in rat brain: implication as neurotrophic factor." Mole. Brain Res.32. 197-210 (1995)

[文献書誌] M.R.Vila: "Hepatocyte growth factor is a potent mitogen for normal human pancreas cells in vitro." Lab. Invest.73. 409-418 (1995)

[文献書誌] P.Gines: "Tyrosine kinase growth factor receptors but not seven-membrane-spanning or phorbol esters activate mitogen-activated protein kinase in rat hepatocytes." Hepatology. 22. 1296-1303 (1995)

[文献書誌] M.Hu: "Human peri-tumoral and lung fibroblasts produce paracrine motility factors for recently established human sarcoma cell strains." Intn. J. Cancer. 62. 585-592 (1995)

[文献書誌] Y.Nakamura: "Expression of local hepatocyte growth factor system in vascular tissue." Biochem. Biophys. Res. Commun.215. 483-488 (1995)

[文献書誌] M.Takahashi: "Hepatocyte growth factor stimulates wound repair of the rabbit esophageal epithelial cells in primary culture." Biochem. Biophys. Res. Commun.216. 298-305 (1995)

[文献書誌] W.G.Jiang: "Induction of tyrosine phosphorylation and translocation of ezrin by hepatocyte growth factor/scatter factor(HGF/SF)." Biochem. Biophys. Res. Commun.217. 1062-1069 (1995)

[文献書誌] T.Kaido: "Continous HGF supply from spleen transplanted HGF-expressing fibroblasts prevents CCl_4-induced acute liver injury in rats." Biochem. Biophys. Res. Commun.218. 1-5 (1996)

[文献書誌] K.Matsumoto: "Hepatocyte growth factor as a renotropic factor and therapeutic potential for acute renal failure." Acute Renal Failure: Emerging New Concepts and Therapeutic Strategies., 24 (1995)

[文献書誌] H.Amaike: "Takahashi Memorial Forum, Tokyo, 5 November 1994,Excepta Medica International Congress Series 1086" Elsevier Science B. V. Amsterdam., 14 (1995)

[文献書誌] 坂倉照好: "細胞外マトリックス" 羊土社, 13 (1995)

[文献書誌] 中村敏一: "用語ライブラリー:発生・神経" 羊土社, 163 (1996)

[文献書誌] 中村敏一 監訳: "細胞増殖因子(I. A. McKay and I. M. Leigh編)" メディカル・サイエンス インターナショナル, 232 (1995)

[文献書誌] U.Koshimizu: "Liver and Environmental Xenobiotics" Narosa-Elsevier Verlag(in press), (1996)

1995 年度実績報告書

中村敏一大阪大学, 医学部, 教授 (00049397)

[文献書誌] 中村敏一監訳: "細胞増殖因子(I. A. McKay and I. M. Leigh編)" メディカル・サイエンスインターナショナル, 232 (1995)