1993 Fiscal Year Annual Research Report

インジュリン/HGFシステムによる器官再生ならび器官恒常性維持の分子機構

Research Project

Project/Area Number	05404080
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 / hepatocyte growth factor / インジュリン / 肝再生 / 腎再生 / 器官再生 / 増殖因子 / MET
Research Abstract	HGFは私達が肝再生因子の実体として発見した増殖因子であるが、HGFは主に増殖制御や細胞運動の促進、形態形成の誘導などの機能を有するpleiotropic factorであり、肝臓や腎臓、肺など多くの組織・器官の形成や再生を担うorganotropic factorである。本年度はインジュリンの精製を進めるとともに,HGFの発現を調節するサイトカインの同定,HGFのさらに多様な働きが明らかになるとともに、HGF/インジュリンシステムからみた癌と宿主の相互作用の理解に貢献できる研究成果が得られた。 (1)インジュリンの精製とHGF発現調節ブタ肺からインジュリンの精製を進める過程でインジュリン活性を示す数種の画分を得た。そのうち2つの画分について精製すると、1つはIL-1であり、他の1つはヘパリンであることが明らかになり、ヘパリンやIL-1がHGF誘導活性を持つことを明らかにした。さらにインジュリンの逆作用を持つHGF発現抑制因子としてTGF-β1やグルココルチコイドが明らかになり、HGF発現がアクセルとブレーキにより巧妙に調節されていることが考えられた。現在さらに未知のタンパク質性のインジュリン活性の精製を進めている。 (2)新たに明らかになったHGFの生物活性 HGFは間葉に由来し上皮に働きかける因子と考えられてきたが、HGFが間葉組織由来細胞にも生物活性を発揮することを明らかにした。その1つは造血幹細胞の増殖促進作用ならびに血小板増加作用である。2つ目は前破骨細胞の増殖促進と破骨細胞への分化促進作用である。すなわちHGFにbone-remodeling作用があるという結果である。3つ目は関節軟骨の増殖と分化を強く促す作用である。 (3)インジュリン発現を介するがん細胞と宿主細胞との相互作用がん細胞の増殖能や浸潤転移能が宿主細胞の影響を強く受けていることは古くから知られている。この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。がん細胞の中にHGF誘導因子(インジュリン様因子)を分泌するものが高頻度で検出された。がん細胞がインジュリン様因子を産生して宿主ストロマー細胞のHGF産生を促し、このHGFによりがん細胞の増殖能や浸潤能、線腔形成能が高まる可能性がある。HGFとそのインデュサーであるインジュリンをメディエーターとしてがんの増殖、悪性化などがん-宿主相関についての分子レベルの理解ができると考えている。

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 CC14-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 factohuman 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: "Molecular characteristics of HGF and gene,and its biochemical aspects." Birkhauser Verlag, 1-29 (1993)
[Publications] K.Matsumoto: "Roles of HGF as a pleiotropic factor in organ regeneration." Birkhauser Verlag, 225-249 (1993)
[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

インジュリン/HGFシステムによる器官再生ならび器官恒常性維持の分子機構

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 CC14-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 factohuman 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: "Molecular characteristics of HGF and gene,and its biochemical aspects." Birkhauser Verlag, 1-29 (1993)

[Publications] K.Matsumoto: "Roles of HGF as a pleiotropic factor in organ regeneration." Birkhauser Verlag, 225-249 (1993)

[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)