1993 Fiscal Year Annual Research Report

肝細胞増殖制御の分子機構

Research Project

Project/Area Number	04253231
Research Institution	Osaka University
Principal Investigator	中村敏一大阪大学, 医学部, 教授 (00049397)
Co-Investigator(Kenkyū-buntansha)	水野健作九州大学, 理学部, 助教授 (70128396) 松本邦夫大阪大学, 医学部, 助手 (90201780)
Keywords	HGF / インシュリン
Research Abstract	本年度はHGFの多様な生物活性、細胞のがん化や癌と宿主の相互作用、HGFのin vivo効果をはじめ肝線維化・肝硬変の防止効果、腎不全の治療効果などの成果を得た。 (1)HGFは間葉組織由来の細胞が産生し、上皮細胞に働きかける因子と考えられてきたが、HGFが造血幹細胞,前破骨細胞、間接軟骨や好中球などの間葉組織由来細胞にも作用しユニークな生物活性を発揮することを明らかにした。 (2)一般にHGF産生能とHGF応答能は別々であり、同一細胞で両者が発現し両機能を持つことはない。しかし同一細胞内で人工的に両機能を発現させてやると、細胞ががん化することが明らかになった。 (3)がん細胞と宿主細胞の相互作用をメディエートする液性因子の1つがHGFであることを明らかにした。 (4)制がん剤,シスプラチンは重篤な腎傷害、腎不全を起こす副作用を持つ。腎再生因子としての役割が明らかにされているHGFにラットやマウスを使った実験からシスプラチンの副作用を軽減防止する作用があることを明らかにした。 (5)ラットに肝臓毒DMNを極微量5週間投与すると肝線維化が進み、典型的な肝硬変を発症する。この時HGFを投与すると、肝線維化が著しく抑制され肝硬変の発症が強く防止された。 (6)ブタ肺からインシュリンの精製を進める過程でインシュリン活性を示す数種の画分を得た。そのうち2つの画分のうち、1つはインタロイキン-1であり、他の1つはヘパリンであることを明らかにした。 (7)プロHGFのArg^<494>-Val^<495>部位を特異的に切断する分子量約90kDaの新しいプロテアーゼをウシ血清中から精製して、HGF-converting enzymeと名付けた。 (8)c-metのfamilyをクローニングする過程で、脳で発現が見られる2種類の新しいプロテインキナーゼを見い出した。1つはレセプター型チロシンキナーゼであり、Skyと命名した。他の1つはLIMドメインを2個有し、C末にチロンシン型とセリン/スレオニン型のキナーゼドメインを持つユニークなプロティンキナーゼでLIMキナーゼと名付けた。

Research Products
(51 results)

All Other

All Publications (51 results)

[Publications] T.Igawa: "Hepatocyte growth factor may function as a renotropic factor for regeneration in rats with acute renal injury." Am.J.Physiol.265. F61-69 (1993)
[Publications] K.Mizuno: "Proteolytic activation of single-chain precursor of hepatocyte growth factor by extracellular serine protease." Biochem.Biophys.Res.Commun.189. 1631-1638 (1993)
[Publications] A.Shimamoto: "Hepatocyte growth factor-like protein is identical to macrophage stimulating protein." FEBS Lett.333. 61-66 (1993)
[Publications] K.Mizuno: "Cell density-dependent regulation of HGF receptor on adult rat hepatocytes in primary culture." J.Biochem.114. 96-102 (1993)
[Publications] K.Mizuno: "Hepatocyte growth factor stimulate growth of hematopoietic progenitor cells." Biochem.Biophys.Res.Commun.194. 178-186 (1993)
[Publications] R.C.Harris: "Hepatocyte growth factor is mitogenic for cultured renal epithelial cells." Life Science. 52. 1091-1100 (1993)
[Publications] K.Ryggard: "Expression of the protooncogenes c-met and c-kit and their ligands hepatocyte growth factor/scatter factor and stem cell factor,in SCLC cell lines and xenografts" Brit.J.Cancer. 67. 37-46 (1993)
[Publications] A.Koj: "Regulation of synthesis of some proteinase inhibitors in human hepatoma cells HepG2 by cytokines,hepatocyte growth factor and retinoicacid." Biol.Chem.Hoppe-Seyler. 374. 193-201 (1993)
[Publications] K.Liu: "Decrease in the hepatic uptake clearance of hepatocyte growth factor(HGF)in CCl4-intoxicated rats." Hepatology. 17. 651-660 (1993)
[Publications] H.Hara: "Hepatocyte growth factor is linked by o-glycosylated oligosaccharide on the α-chain." Biochem.Biophys.Res.Commun.189. 1329-1335 (1993)
[Publications] M.Johnson: "HGF induces proliferation and morphogenesis in nonparenchymal epithelial liver cells." Hepatology. 17. 1052-1061 (1993)
[Publications] S.P.Seslar: "Regulation of fibroblast hepatocyte growth factor/scatter factor expression by human breast carcinoma cell lines and peptide growth factor." Cancer Res.58. 1233-1238 (1993)
[Publications] W.G.Jiang: "Regulation of spreading and growth of colon cancer cells by hepatocyte growth factor." Clin.& Exp.Metastasis. 11. 235-242 (1993)
[Publications] M.Watabe: "Cooperative action of hepatocyte growth factor and anti-cadherin antibody on the scattering and growth of keratinocite lines." Cell Structure Functions. 18. 117-124 (1993)
[Publications] Y.Okano: "Tyrosine phosphorylation of hospholipase-Cr in c-met/HGF receptor-stimulated hepatocytes:Comparison with HepG2 hepatocarcinoma cells." Biochem.Biophys.Res.Commun.190. 842-848 (1993)
[Publications] H.Ogasawara: "Enhanced expression of hepatocyte growth factor and c-Met mRNAs in isografts in exprimental rat liver transplants." Transplantation Proceedings. 25. 149-151 (1993)
[Publications] H.Hara: "Structural study of the N-linked oligosaccharides of hepatocyte growth factor by two-dimensional sugar mapping." J.Biochem.114. 76-82 (1993)
[Publications] K.Rygaard: "Growth inhibition and change in morphology and motility of SCLC cell lines by hepatocyte growth factor/scatter factor." Intern.J.Oncology. 2. 991-996 (1993)
[Publications] T.Kohira: "Identification of a biologically functional novel 1L-1β-specific receptor on adult rat hepatocytes." J.Biochem.114. 658-662 (1993)
[Publications] Y.Yoshinaga: "Immunohistochemical detection of hepatocyte growth factor/scatter factor in human cancerous and inflammatory lesions of various organs." Jap.J.Cancer Res.84. 1150-1158 (1993)
[Publications] M.Masuhara: "Cyclosporine stimulates hepatocyte proliferation and accelerates development of hepatocellular carcinomas in rats." Carcinogenesis. 14. 1579-1584 (1993)
[Publications] I.Okano: "Cloning of CRP2,a novel member of cystein-rich protein family with two repeats of an unusual LIM/double Zincfinger motif." FEBS Lett.333. 51-55 (1993)
[Publications] T.Mitaka: "Effect of mitogens and co-mitogens on the formation of small-cell colonies in primary cultures of rat hepatocytes." J.Cell.Physiol.157. 461-463 (1993)
[Publications] K.Takaishi: "Involvement of rho p21 small GTP-binding protein and its regulatory protein in the HGF-induced cell motility." Oncogene. 9. 273-279 (1994)
[Publications] M.Takahashi: "Hepatocyte growth factor induces mitogenic reaction to the rabbit gastric epithelial cells in primary culture." Biochem.Biophys.Res.Commun.191. 528-534 (1993)
[Publications] S.Rong: "Autocrine tumorigenesis in NIH/3T3 cells by the human hepatocyte growth factor human met protooncogene lead to high levels of expression of the ligand and receptor." Cell Growth and Differentiation. 4. 563-569 (1993)
[Publications] H.Kanda: "Hepatocyte growth factor transforms immortalized mouse liver epithelial cells." Oncogene. 8. 3047-3053 (1993)
[Publications] M.-S.Tsao: "Hepatocyte growth factor is an autocrine factor for human normal bronchial epithelial and lung carcinoma cells." Cell Growth and Differentiation. 4. 571-579 (1993)
[Publications] K.Yanagita: "Marked expression of hepatocyte growth factor gene and rapid down-regulation of the receptor before onset of lung regeneration after lung injury." J.Biol.Chem.268. 21212-21217 (1993)
[Publications] K.Matsumoto: "Heparin as an inducer of hepatocyte growth factor." J.Biochem.114. 820-826 (1993)
[Publications] K.Mizuno: "Hairpin loop and second kringle domain are essential sites for heparin-binding and biological activity of hepatocyte growth factor." J.Biol.Chem.(in press). (1994)
[Publications] G.Shiota: "Hepatocyte growth factor accelerates liver regeneration and causes a hepatoproliferative disorder in transgenic mice." Hepatology. (in press). (1994)
[Publications] S.Bellusci: "Creation of an HGF/SF autocrine loop in carcinoma cells induces invasive properties associated with increased oncogenic potential." Oncogene. (in press). (1994)
[Publications] O.Amano: "Expression and localization of hepatocyte growth factor in rat submandibular gland." Growth Factors. (in press). (1994)
[Publications] K.Ohashi: "Cloning of novel receptor tyrosine kinase,Sky,predominantly expressed in brain." Oncogene. (in press.). (1994)
[Publications] H.Okazaki: "Prtial purification and characterization of“Injurin-like factor"which stimulates production of hepatocyte growth factor." Biochem.Biophys.Acta.(in press). (1994)
[Publications] Y.Kato: "Heparin-hepatocyte growth factor(HGF)complex with low plasma clearance and retained hepatocyte proliferating activity." Hepatology. (in press). (1994)
[Publications] K.Mizuno: "Purification and characterization of hepatocyte growth factor(HGF)-converting enzyme:Activation of Pro HGF." Biochem.Biophys.Res.Commun.(in press). (1994)
[Publications] H.Chang: "Blood hepatocyte growth factor levels inchronic renal failure patients." Nephron. (in press). (1994)
[Publications] G.Shiota: "Autocrine stimulation of glioblastoma cells resulting from expression of c-met and the met-ligand(Scatter factor/Hepatocyte growth factor)." Oncogene. (in press). (1994)
[Publications] K.Kawaida: "Hepatocyte growth factor prevent acute renal failure and accelerate renal regeneration." Proc.Nalt.Acad.Sci.USA. (in press). (1994)
[Publications] J.J.Couper: "High glucose and hyperosmolality stimulate hepatocyte growth factor secrection from cultured human mesangial cells." Diabetologia. (in press). (1994)
[Publications] R.J.Mason: "Hepatocyte growth factor is a growth factor for rat alveolar type II cells." Am.J.Respir.Cell Mol.Biol.(in press). (1994)
[Publications] Y.Itakura: "Autocrine stimulation of motility in SBC-5 human lung carcinom cells by a two-kringl variant of HGF." Cancer Lett.(in press). (1994)
[Publications] M.Lyon: "The interaction of hepatocyte growth factor with heparan sulphate;Elucidation of the major heparan sulphate structural determinants." J.Biol.Chem.(in press). (1994)
[Publications] K.Matsumoto: "Pleiotropic roles of HGF in mitogenesis,morphogenesis and organ regeneration." Gann Monograph No.42:Growth Factors;Cell Growth,Morphogenesis and Transformation(edts.T.Nakamura & K.Matsumoto). (in press). (1994)
[Publications] T.Nakamura: "Hepatocyte growth factor as mitogen,motogen and morphogen,and its roles in organ regeneration." Proceedings of the 24th International Symposium of the Princess Takamatsu Cancer Research Fund,Princeton Scientific.New Jersey. (in press). (1994)
[Publications] K.Mizuno: "“Hepatocyte Growth Factor-Scatter Factor and c-Met Receptor"(ed.I.D.Goldberg)Birkhauser Verlag,pp." Molecular characteristics of HGF and gene,and its biochemical aspects.,
[Publications] K.Matsumoto: "“Hepatocyte Growth Factor-Scatter Factor and c-Met Receptor"(ed.I.D.Goldberg)Birkhauser Verlag" Roles of HGF as a pleiotropic factor in organ regeneration.,
[Publications] K.Matsumoto: "Primary and continuous cell culture:Collagenase and Hyaluronidase." John Wiley & Sons(in press), (1993)
[Publications] T.Nakamura: "Hepatocyte growth factor:Mitogen,motogen,morphogen,and its roles in tissue regeneration." Elsevier Science Publishers, 313-320 (1993)

1993 Fiscal Year Annual Research Report

肝細胞増殖制御の分子機構

Principal Investigator

中村 敏一 大阪大学, 医学部, 教授 (00049397)

Research Products

[Publications] T.Igawa: "Hepatocyte growth factor may function as a renotropic factor for regeneration in rats with acute renal injury." Am.J.Physiol.265. F61-69 (1993)

[Publications] K.Mizuno: "Proteolytic activation of single-chain precursor of hepatocyte growth factor by extracellular serine protease." Biochem.Biophys.Res.Commun.189. 1631-1638 (1993)

[Publications] A.Shimamoto: "Hepatocyte growth factor-like protein is identical to macrophage stimulating protein." FEBS Lett.333. 61-66 (1993)

[Publications] K.Mizuno: "Cell density-dependent regulation of HGF receptor on adult rat hepatocytes in primary culture." J.Biochem.114. 96-102 (1993)

[Publications] K.Mizuno: "Hepatocyte growth factor stimulate growth of hematopoietic progenitor cells." Biochem.Biophys.Res.Commun.194. 178-186 (1993)

[Publications] R.C.Harris: "Hepatocyte growth factor is mitogenic for cultured renal epithelial cells." Life Science. 52. 1091-1100 (1993)

[Publications] K.Ryggard: "Expression of the protooncogenes c-met and c-kit and their ligands hepatocyte growth factor/scatter factor and stem cell factor,in SCLC cell lines and xenografts" Brit.J.Cancer. 67. 37-46 (1993)

[Publications] A.Koj: "Regulation of synthesis of some proteinase inhibitors in human hepatoma cells HepG2 by cytokines,hepatocyte growth factor and retinoicacid." Biol.Chem.Hoppe-Seyler. 374. 193-201 (1993)

[Publications] K.Liu: "Decrease in the hepatic uptake clearance of hepatocyte growth factor(HGF)in CCl4-intoxicated rats." Hepatology. 17. 651-660 (1993)

[Publications] H.Hara: "Hepatocyte growth factor is linked by o-glycosylated oligosaccharide on the α-chain." Biochem.Biophys.Res.Commun.189. 1329-1335 (1993)

[Publications] M.Johnson: "HGF induces proliferation and morphogenesis in nonparenchymal epithelial liver cells." Hepatology. 17. 1052-1061 (1993)

[Publications] S.P.Seslar: "Regulation of fibroblast hepatocyte growth factor/scatter factor expression by human breast carcinoma cell lines and peptide growth factor." Cancer Res.58. 1233-1238 (1993)

[Publications] W.G.Jiang: "Regulation of spreading and growth of colon cancer cells by hepatocyte growth factor." Clin.& Exp.Metastasis. 11. 235-242 (1993)

[Publications] M.Watabe: "Cooperative action of hepatocyte growth factor and anti-cadherin antibody on the scattering and growth of keratinocite lines." Cell Structure Functions. 18. 117-124 (1993)

[Publications] Y.Okano: "Tyrosine phosphorylation of hospholipase-Cr in c-met/HGF receptor-stimulated hepatocytes:Comparison with HepG2 hepatocarcinoma cells." Biochem.Biophys.Res.Commun.190. 842-848 (1993)

[Publications] H.Ogasawara: "Enhanced expression of hepatocyte growth factor and c-Met mRNAs in isografts in exprimental rat liver transplants." Transplantation Proceedings. 25. 149-151 (1993)

[Publications] H.Hara: "Structural study of the N-linked oligosaccharides of hepatocyte growth factor by two-dimensional sugar mapping." J.Biochem.114. 76-82 (1993)

[Publications] K.Rygaard: "Growth inhibition and change in morphology and motility of SCLC cell lines by hepatocyte growth factor/scatter factor." Intern.J.Oncology. 2. 991-996 (1993)

[Publications] T.Kohira: "Identification of a biologically functional novel 1L-1β-specific receptor on adult rat hepatocytes." J.Biochem.114. 658-662 (1993)

[Publications] Y.Yoshinaga: "Immunohistochemical detection of hepatocyte growth factor/scatter factor in human cancerous and inflammatory lesions of various organs." Jap.J.Cancer Res.84. 1150-1158 (1993)

[Publications] M.Masuhara: "Cyclosporine stimulates hepatocyte proliferation and accelerates development of hepatocellular carcinomas in rats." Carcinogenesis. 14. 1579-1584 (1993)

[Publications] I.Okano: "Cloning of CRP2,a novel member of cystein-rich protein family with two repeats of an unusual LIM/double Zincfinger motif." FEBS Lett.333. 51-55 (1993)

[Publications] T.Mitaka: "Effect of mitogens and co-mitogens on the formation of small-cell colonies in primary cultures of rat hepatocytes." J.Cell.Physiol.157. 461-463 (1993)

[Publications] K.Takaishi: "Involvement of rho p21 small GTP-binding protein and its regulatory protein in the HGF-induced cell motility." Oncogene. 9. 273-279 (1994)

[Publications] M.Takahashi: "Hepatocyte growth factor induces mitogenic reaction to the rabbit gastric epithelial cells in primary culture." Biochem.Biophys.Res.Commun.191. 528-534 (1993)

[Publications] S.Rong: "Autocrine tumorigenesis in NIH/3T3 cells by the human hepatocyte growth factor human met protooncogene lead to high levels of expression of the ligand and receptor." Cell Growth and Differentiation. 4. 563-569 (1993)

[Publications] H.Kanda: "Hepatocyte growth factor transforms immortalized mouse liver epithelial cells." Oncogene. 8. 3047-3053 (1993)

[Publications] M.-S.Tsao: "Hepatocyte growth factor is an autocrine factor for human normal bronchial epithelial and lung carcinoma cells." Cell Growth and Differentiation. 4. 571-579 (1993)

[Publications] K.Yanagita: "Marked expression of hepatocyte growth factor gene and rapid down-regulation of the receptor before onset of lung regeneration after lung injury." J.Biol.Chem.268. 21212-21217 (1993)

[Publications] K.Matsumoto: "Heparin as an inducer of hepatocyte growth factor." J.Biochem.114. 820-826 (1993)

[Publications] K.Mizuno: "Hairpin loop and second kringle domain are essential sites for heparin-binding and biological activity of hepatocyte growth factor." J.Biol.Chem.(in press). (1994)

[Publications] G.Shiota: "Hepatocyte growth factor accelerates liver regeneration and causes a hepatoproliferative disorder in transgenic mice." Hepatology. (in press). (1994)

[Publications] S.Bellusci: "Creation of an HGF/SF autocrine loop in carcinoma cells induces invasive properties associated with increased oncogenic potential." Oncogene. (in press). (1994)

[Publications] O.Amano: "Expression and localization of hepatocyte growth factor in rat submandibular gland." Growth Factors. (in press). (1994)

[Publications] K.Ohashi: "Cloning of novel receptor tyrosine kinase,Sky,predominantly expressed in brain." Oncogene. (in press.). (1994)

[Publications] H.Okazaki: "Prtial purification and characterization of“Injurin-like factor"which stimulates production of hepatocyte growth factor." Biochem.Biophys.Acta.(in press). (1994)

[Publications] Y.Kato: "Heparin-hepatocyte growth factor(HGF)complex with low plasma clearance and retained hepatocyte proliferating activity." Hepatology. (in press). (1994)

[Publications] K.Mizuno: "Purification and characterization of hepatocyte growth factor(HGF)-converting enzyme:Activation of Pro HGF." Biochem.Biophys.Res.Commun.(in press). (1994)

[Publications] H.Chang: "Blood hepatocyte growth factor levels inchronic renal failure patients." Nephron. (in press). (1994)

[Publications] G.Shiota: "Autocrine stimulation of glioblastoma cells resulting from expression of c-met and the met-ligand(Scatter factor/Hepatocyte growth factor)." Oncogene. (in press). (1994)

[Publications] K.Kawaida: "Hepatocyte growth factor prevent acute renal failure and accelerate renal regeneration." Proc.Nalt.Acad.Sci.USA. (in press). (1994)

[Publications] J.J.Couper: "High glucose and hyperosmolality stimulate hepatocyte growth factor secrection from cultured human mesangial cells." Diabetologia. (in press). (1994)

[Publications] R.J.Mason: "Hepatocyte growth factor is a growth factor for rat alveolar type II cells." Am.J.Respir.Cell Mol.Biol.(in press). (1994)

[Publications] Y.Itakura: "Autocrine stimulation of motility in SBC-5 human lung carcinom cells by a two-kringl variant of HGF." Cancer Lett.(in press). (1994)

[Publications] M.Lyon: "The interaction of hepatocyte growth factor with heparan sulphate;Elucidation of the major heparan sulphate structural determinants." J.Biol.Chem.(in press). (1994)

[Publications] K.Matsumoto: "Pleiotropic roles of HGF in mitogenesis,morphogenesis and organ regeneration." Gann Monograph No.42:Growth Factors;Cell Growth,Morphogenesis and Transformation(edts.T.Nakamura & K.Matsumoto). (in press). (1994)

[Publications] T.Nakamura: "Hepatocyte growth factor as mitogen,motogen and morphogen,and its roles in organ regeneration." Proceedings of the 24th International Symposium of the Princess Takamatsu Cancer Research Fund,Princeton Scientific.New Jersey. (in press). (1994)

[Publications] K.Mizuno: "“Hepatocyte Growth Factor-Scatter Factor and c-Met Receptor"(ed.I.D.Goldberg)Birkhauser Verlag,pp." Molecular characteristics of HGF and gene,and its biochemical aspects.,

[Publications] K.Matsumoto: "“Hepatocyte Growth Factor-Scatter Factor and c-Met Receptor"(ed.I.D.Goldberg)Birkhauser Verlag" Roles of HGF as a pleiotropic factor in organ regeneration.,

[Publications] K.Matsumoto: "Primary and continuous cell culture:Collagenase and Hyaluronidase." John Wiley & Sons(in press), (1993)

[Publications] T.Nakamura: "Hepatocyte growth factor:Mitogen,motogen,morphogen,and its roles in tissue regeneration." Elsevier Science Publishers, 313-320 (1993)

中村敏一大阪大学, 医学部, 教授 (00049397)