1992 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	Kyushu University
Principal Investigator	中村敏一九州大学, 理学部, 教授 (00049397)
Co-Investigator(Kenkyū-buntansha)	松本邦夫九州大学, 理学部, 助手 (90201780) 原野友之九州大学, 理学部, 助手 (80037275) 水野健作九州大学, 理学部, 助教授 (70128396)
Keywords	肝細胞増殖因子 / HGF / 肝再生因子 / 腎再生因子 / インジュリン / c-met
Research Abstract	私達は、初代培養肝細胞に対する最も強力な増殖促進因子である肝細胞増殖因子(HGF)の単離とcDNAクローニングによる全一次構造解析にはじめて成功した。本研究では、HGFの機能、レセプター解析、および発現調節機構について以下の点を明らかにした。 1)HGFが肝再生因子として作用することをin vivoで証明した。リコンビナントHGFを30%部分肝切除マウスに尾静脈投与すると、投与量に応じて肝再生が強く引き起こされた。また、HGFは肝細胞の増殖促進だけでなく、肝臓毒であるANITにより誘起された肝炎に対して抗肝災、肝細胞保護作用をもつことを明らかにした。 2)HGFが腎臓毒や腎虚血などの腎傷害に対して腎再生因子として作用することを明らかにした。腎傷害マウスにHGFを投与すると、腎再生が強く促進されるとともに、腎不全の防止、腎機能の保護作用が認められ、HGFの腎再生因子および抗腎炎因子としての機能がin vivoで証明された。 3)HGFの発現調節機構の解明。器官の傷害に伴ってHGFの発現が誘導される。私達は肝傷害時のラット血中に出現する熱および酸処理に安定なHGF発現誘導因子(インジュリン)を見出し、部分精製した。また、インジュリンとは別に、IL-1やTNF-αがHGF mRNAの発現を誘導し、逆にTGF-β1やグルココルチコイドはHGF mRNAの発現を強く抑制した。また、ヘパリンがHGFの産生誘導を引き起こすことも明らかにした。このように、HGFの発現は様々な因子によって調節を受けており、傷害後の器官再生や創傷治癒が過不足なく起こるような機構が存在していると考えられる。 4)c-metプロトオンコジーン産物をCOS細胞に発現させ、これがHGFの高親和性で増殖シグナルを伝達できるレセプターであることを証明した。

Research Products
(19 results)

All Other

All Publications (19 results)

[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)
[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)
[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)
[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)
[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)
[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)
[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)
[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)
[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)
[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)
[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)
[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)
[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)
[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)
[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)
[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)
[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)
[Publications] K.Mizuno and T.Nakamura: "Hepatocyte Growth Factor-Scatter Factor and C-Met Receptor(分担)" Birkhauser Verlag, 1-29 (1993)
[Publications] K.Matsumoto and T.Nakamura: "Hepatocyte Growth Factor-Scatter Factor and C-Met Receptor(分担)" Birkhauset Verlag, 225-249 (1993)

1992 Fiscal Year Annual Research Report

肝細胞増殖制御の分子機構

Principal Investigator

中村 敏一 九州大学, 理学部, 教授 (00049397)

Research Products

[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)

[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)

[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)

[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)

[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)

[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)

[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)

[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)

[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)

[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)

[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)

[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)

[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)

[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)

[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)

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

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

中村敏一九州大学, 理学部, 教授 (00049397)