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肝細胞増殖制御の分子機構

Research Project

Project/Area Number 04253231
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Research InstitutionOsaka University (1993)
Kyushu University (1992)

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)
原野 友之  九州大学, 理学部, 助手 (80037275)
Project Period (FY) 1991 – 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥37,000,000 (Direct Cost: ¥37,000,000)
Fiscal Year 1993: ¥22,000,000 (Direct Cost: ¥22,000,000)
Fiscal Year 1992: ¥15,000,000 (Direct Cost: ¥15,000,000)
KeywordsHGF / インシュリン / 肝細胞増殖因子 / 肝再生因子 / 腎再生因子 / インジュリン / c-met
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。

Report

(2 results)
  • 1993 Annual Research Report
  • 1992 Annual Research Report
  • Research Products

    (70 results)

All Other

All Publications (70 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)

    • Related Report
      1993 Annual Research Report
  • [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)

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

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

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

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

    • Related Report
      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [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)

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

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

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

    • Related Report
      1993 Annual Research Report
  • [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)

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

    • Related Report
      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [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)

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

    • Related Report
      1993 Annual Research Report
  • [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)

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

    • Related Report
      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [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)

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

    • Related Report
      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [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)

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

    • Related Report
      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [Publications] G.Shiota: "Hepatocyte growth factor accelerates liver regeneration and causes a hepatoproliferative disorder in transgenic mice." Hepatology. (in press). (1994)

    • Related Report
      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [Publications] O.Amano: "Expression and localization of hepatocyte growth factor in rat submandibular gland." Growth Factors. (in press). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] K.Ohashi: "Cloning of novel receptor tyrosine kinase,Sky,predominantly expressed in brain." Oncogene. (in press.). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] H.Okazaki: "Prtial purification and characterization of“Injurin-like factor"which stimulates production of hepatocyte growth factor." Biochem.Biophys.Acta.(in press). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Y.Kato: "Heparin-hepatocyte growth factor(HGF)complex with low plasma clearance and retained hepatocyte proliferating activity." Hepatology. (in press). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] K.Mizuno: "Purification and characterization of hepatocyte growth factor(HGF)-converting enzyme:Activation of Pro HGF." Biochem.Biophys.Res.Commun.(in press). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] H.Chang: "Blood hepatocyte growth factor levels inchronic renal failure patients." Nephron. (in press). (1994)

    • Related Report
      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [Publications] K.Kawaida: "Hepatocyte growth factor prevent acute renal failure and accelerate renal regeneration." Proc.Nalt.Acad.Sci.USA. (in press). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] J.J.Couper: "High glucose and hyperosmolality stimulate hepatocyte growth factor secrection from cultured human mesangial cells." Diabetologia. (in press). (1994)

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      1993 Annual Research Report
  • [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)

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      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [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)

    • Related Report
      1993 Annual Research Report
  • [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.,

    • Related Report
      1993 Annual Research Report
  • [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.,

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

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

    • Related Report
      1993 Annual Research Report
  • [Publications] G.Shiota,D.B.Rhoads,T.C.Wang,T.Nakamura and E.V.Schmidt: "Hepatocyte growth factor inhibits growth of hepatocellular carcinomacells." Proc.Natl.Acad.Sci.USA. 89,. 373-377 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] H.Tajima,O.Higuchi,K.Mizuno and T.Nakamura: "Tissue distribution of hepatocyte growth factor receptor and its exclusive down-regulation in a regenerating organ after injury." J.Biochem.111,. 401-406 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] K.Yanagita,M.Nagaike,H.Ishibashi,Y.Niho,K.Matsumoto and T.Nakamura: "Lung may have an endocrine function producing hepatocyte growth factor in response to injury of distal organs." Biochem.Biophys.Res.Commun.182,. 802-809 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] S.Osada,S.Nakashima,S.Saji,T.Nakamura,and Y.Nozawa: "Hepatocyte growth factor(HGF)mediates the sustained formation of 1,2-diacylglycerol via phosphatidylcholine-phospholipase C in cultured rat hepatocytes." FEBS.Lett.297,. 271-274 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] K.Matsumoto,H.Tajima,M.Hamanoue,S.Kono,T.Kinoshita and T.Nakamura: "Identification and characterization of ¨injurin¨,an inducer of expression of the gene for hepatocyte growth factor." Proc.Natl.Acad.Sci.USA,. 89,. 3800-3804 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] G.Ramadori,K.Neubauer,M.Odenthal,T.Nakamura,T.Knittel,S.Chwogler,and K.H.Meyer zum Buschenfelde: "Hepatocyte Growth Factor(Hepatopoietin a,Scatter Factor)-Gene is expressed in ¨Quiescent¨Fat-Storing(Ito)cells of rat liver:downregulation by transforming growth factor-b" Biochem.Biophys.Res.Commun.183,. 739-742 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] H.Tajima,K.Matsumoto and T.Nakamura: "Regulation of cell growth and motility by hepatocyte growth factor and receptor expression in various cell species." Exp.Cell Res.202,. 423-431 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] M.Hamanoue,K.Kawaida,S.Takao,H.Shimazu,S.Noji,K.Matsumoto and T.Nakamura: "Expression of the c-met proto-oncogene in COS cells is required for hepatocyte growth factor high affinity binding mitogenic signal transduction." FEBS Lett.301,. 282-286 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] O.Higuchi,K.Mizuno,G.F.Vande Woude and T.Nakamura: "Rapid and marked induction of HGF mRNA in liver and HGF activity in serum of rats after ischemic of crush liver injury." Hepatology. 16,. 1485-1492 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] S.Kono,M.Nagaike,K.Matsumoto,and T.Nakamura: "Marked induction of hepatocyte growth factor mRNA in intact kidney and spleen in response to injury of distan organ." Biochem.Biophys.Res.Commun.186,. 991-998 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] A.J.Marker,E.Galloway,S.Palmer,T.Nakamura,G.W.Gould,R.N.M.MacSween,and M.Bushfield: "Role of the adenylate cyclase,phosphoinositidase c and receptor tyrosine kinase system in the control of hepatocyte proliferation by hepatocyte growth factor." Biochemical.Pharmacol.44,. 1037-1043 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Y.Ishiki,H.Ohnishi,Y.Muto,K.Matsumoto and T.Nakamura: "Direct evidence that hepatocyte growth factor is a hepatotrophic factor for liver regeneration and for potent anti-hepatitis action in vivo." Hepatology. 16,. 1227-1235 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] M.S.Pepper,K.Matsumoto,T.NAkamura,L.Orci and R.Montesano: "Hepatocyte growth factor induces urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in MDCK epithelial cells." J.Biol.Chem.267,. 20493-20496 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] M.Masuhara,S.L.Katyal,T.Nakamura and H.Shinozuka: "Differential expression of hepatocyte growth factor,transforming growth factor-alpha and transforming growth factor-betal mRNAs in two experimental models of liver cell proliferation." Hepatology,. 16,. 1241-1249 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] K.Matsumoto,H.Tajima,H.Okazaki,and T.Nakamura: "Negative regulation of hepatocyte growth factor gene expression in human lung fibroblasts and leukemic cells by transforming growth factor-β1 and glucocorticoids" J.Biol.Chem.267,. 24917-24920 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] M.Kagoshima,T.Kinoshita,T.Matsumoto and T.Nakamura: "Changes in expression of mRNA and receptor for hepatocyte growth factor in liver,kidney and lung during postnatal development in rats." Eur.J.Biochem.210,. 375-380 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] S.Rong,M.Bodescot,D.Blair,J.Dunn,T.Nakamura,K.Mizuno,M.Park,A.Chan,S.Aaronson,and G.F.Vande Woude: "Tumorigenicity of the met protooncogene and the gene for hepatocyte growth factor." Mol.Cell Biol.12,. 5152-5158 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] K.Mizuno and T.Nakamura: "Hepatocyte Growth Factor-Scatter Factor and C-Met Receptor(分担)" Birkhauser Verlag, 1-29 (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] K.Matsumoto and T.Nakamura: "Hepatocyte Growth Factor-Scatter Factor and C-Met Receptor(分担)" Birkhauset Verlag, 225-249 (1993)

    • Related Report
      1992 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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