1991 Fiscal Year Annual Research Report

肝細胞増殖制御の分子機構

Research Project

Project/Area Number	03258230
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 / HGFレセプタ- / 肝再生 / 腎再生 / インジュリン
Research Abstract	肝細胞増殖因子(Hepatocyte Growth Factor,HGF)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り、肝再生因子の本体と考えられる新しい増殖因子である。本研究では、HGFの機能について以下の点を明らかにした。1)肝炎、虚血、挫滅、部分肝切除などの様々な肝障害に伴って、障害を受けた肝臓や血中でHGF mRNAやHGF活性が著しく増加することや、肝細胞膜上のHGFレセプタ-が速やかにdownーregulationすることを明らかにし、HGFが肝再生因子として機能していることを示した。2)HGFは肝細胞ばかりでなく、腎尿細管上皮細胞、皮膚のメラノサイト、ケラチノサイトを含む多くの上皮細胞の増殖を促進することを示した。3)逆に数種の癌細胞に対しては強い増殖抑制活性をもつことを明らかにした。4)細胞の運動性を高める活性(motogen)や腎上皮細胞の管腔形成を促進するモルフォゲンとしての活性をもつことを示して、HGFは多様な生物活性をもつ多機能性増殖因子であることを明らかにした。5)HGFは肝再生因子としてのみならず、片腎摘出や腎臓毒や腎虚血による腎傷害時における腎再生因子の一つとして作用していることを示した。6)部分肝切除後、残余肝におけるHGF mRNAの発現が高まる以前に血中に高いHGF活性が検出されることを見出し、この血中HGFは他臓器に由来するのではないかと予想した。事実、部分肝切除や片腎摘出といった臓器の障害に伴って、全く無傷である肺においてHGF mRNAの速やかな発現誘導が起こることを見出した。7)さらに肝障害に伴い肺のHGF mRNAの発現誘導を促す因子(injurin)の血中での存在を明らかにした。8)HGFレセプタ-については、cーmetプロトオンコジ-ン産物との関連を明らかにするため、cーmet cDNAをCOS細胞に導入し、高親和性で機能的レセプタ-の発現を確認した。9)HGF遺伝子の構造を明らかにした。

Research Products

(33 results)

All Other

All Publications (33 results)

[Publications] K.Matsumoto and T.Nakamura: "Hepatocyte growth factor: molecular structure and implications for a central role in liver regeneration." Jounal of Gastroenterology and Hepatology. 6. 509-519 (1991)
[Publications] T.Seki,M.Hagiya,M.Shimonishi,T.Nakamura and S.Shimizu: "Organizaition of the human hepatocyte growth factorーencoding gene." Gene. 102. 213-219 (1991)
[Publications] T.Igawa,S.Kanda,H.Kanetake,Y.Saitoh,A.Ichihara,Y.Tomita and T.Nakamura: "Hepatocyte growth factor is a potent mitogen for cultured rabbit renal tubular epithelial cells." Biochem.Biophys.Res.Commun.174. 831-838 (1991)
[Publications] O.Asami,I.Ihara,N.Shimizu,S.Shimizu,Y.Tomita,A.Ichihara and T.Nakamura: "Purification and characterization of hepatocyte growth factor from injured liver of carbon tetrachlorideーtreated rats." J.Biochem.109. 8-13 (1991)
[Publications] I.Shimizu,A.Ichihara and T.Nakamura: "Hepatocyte growth factor in ascites from patients with cirrhosis." J.Biochem.109. 14-18 (1991)
[Publications] K.Matsumoto,H.Tajima and T.Nakamura: "Hepatocyte growth factor is a potent stimulator for human melanocyte DNA synthesis and growth." Biochem.Biophys.Res.Commun.176. 45-51 (1991)
[Publications] O.Higuchi and T.Nakamura: "Identification and change in the receptor for hepatocyte growth factoス in rat liver after partial hepatectomy or induced hepatitis." Biocem.Biophys.Res.Commun.176. 599-607 (1991)
[Publications] T.Kinoshita,S.Hirao,K.Matsumoto and T.Nakamura: "Possible endocrine control by hepatocyte growth factor of liver regeneration after partial hepatectomy." Biochem.Biophys.Res.Commun.177. 330-335 (1991)
[Publications] A.Kumatori,T.Nakamura and A.Ichihara: "Cellーdensity dependent expression of the cーmyc gene in primary cultured rat hepatocytes." Biochem.Biophys.Res.Commun.178. 480-485 (1991)
[Publications] K.Matsumoto,K.Hashimoto,K.Yoshikawa and T.Nakamura: "Marked stimulation of growth and motility of human keratinocytes by hepatocyte growth factor." Exp.Cell Res.196. 114-120 (1991)
[Publications] O.Amano,T.Tsuji,T.Nakamura and S.Iseki: "Expression of transforming growth factor bl in the submandibular gland of the rat." J.Histochem.Cytochem.39. 1707-1711 (1991)
[Publications] T.Nakamura: "Structure and function of hepatocyte growth factor." Prog.Growth Factor Res.3. 67-85 (1991)
[Publications] R.A.Furlong,T.Takehara,W.G.Taylor,T.Nakamura and J.S.Rubin: "Comparison of biological and immunoーchemical properties indicates that scatter factor and hepatocyte growth factor are indistinguishable." J.Cell Sci.100. 173-177 (1991)
[Publications] M.Nagaike,S.Hirao,H.Tajima,S.Noji,S.Taniguchi,K.Matsumoto and T.Nakamura: "Renotropic functions of hepatocyte growth factor in renal regeneration after unilateral nephrectomy." J.Biol.Chem.266. 22781-22784 (1991)
[Publications] H.Tajima,K.Matsumoto and T.Nakamura: "Hepatocyte growth factor has potent antiーproliferative activity in various tumor cell lines." FEBS Lett.291. 229-232 (1991)
[Publications] T.Takehara and T.Nakamura: "Protective effect of hepatocyte growth factor on in vitro hepatitis in primary cultured hepatocytes." Biomed.Res.12. 335-338 (1991)
[Publications] T.Konishi,T.Takehara,T.Tsuji,K.Ohsato,K.Matsumoto and T.Nakamura: "Scatter factor from human embryonic lung fibroblasts is probably identical to hepatoーcyte growth factor." Biochem.Biophys.Res.Commun.80. 765-773 (1991)
[Publications] R.Montesano,K.Matsumoto,T.Nakamura and L.Orci: "Identification of a fibroblastーderived epitheー lial morphogen as hepatocyte growth factor." Cell. 67. 901-908 (1991)
[Publications] K.Matsumoto,T.Takehara,H.Inoue,M.Hagiya,S.Shimizu and T.Nakamura: "Deletion of krngle domains or the Nーterminal hairpin structure in hepatocyte growth factor results in marked decreases in related biological activities." Biochem.Biopys.Res.Commun.181. 691-699 (1991)
[Publications] T.Mine,I.Kojima,E.Ogata and T.Nakamura: "Comparison of effects of HGF and EGF on cellular calcium in rat hepatocytes." Biochem.Biophys.Res.Commun.181. 1173-1180 (1991)
[Publications] G.Shiota,D.B.Rhoads,T.C.Wang,T.Nakamura and Emmentt V.Schmidt: "Hepatocyte growth factor inhibits growth of hepatocellular carcinoma cells." Proc.Natl.Acad.Sci.USA. 89. 373-377 (1992)
[Publications] K.Matsumoto and N.Nakamura: "Hepatocyte growth factor: molecular structure,roles in liver regeneration,and other biological functions." Crit.Rev.Oncogenesis. 3. 27-54 (1992)
[Publications] G.Ramadori,K.Neubauer,M.Odenthal,T.Nakamura,T.Knittel,S.Schwogler and K.ーH.Meyer zum: "Hepatocyte growth factor (hepatopoietin a,scatter factor) gene is expressed in “quiescent" fatーstoring (Ito) cells of rat liver: downーregulation by transforming growth factorーb" Buschenfelde Biochem.Biophys.Res.Commun.(1992)
[Publications] S.Ekberg,M.Luther,T.Nakamura and J.ーO.Jansson: "Growth hormone promotes early intiation of hepatocyte growth factor gene expression and DNA synthesis in rat liver after partial hepatectomy." J.Endocrinol.(1992)
[Publications] T.Kamalati,B.Thirunovukarasu,A.Wallace,N.Holder,R.Brooks,T.Nakamuta,E.Gerardi and L.Buluwela: "Downーregulation of scatter factor in MRC 5 fibroblasts by epithelialーderived cells." J.Cell Sci.101. (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. (1992)
[Publications] H.Tajima,O.Higuchi,K.Mizuno and T.Nakamura: "Tissue distribution of hepatocyte growth factor receptor and its exclusive downーregulation in a regenerating organ after the injury." J.Biochem.111. (1992)
[Publications] M.Bhargava,A.Joseph,Y.Li,S.Pang,I.Goldberg,E.Setter,M.A.Donovan,R.Zarnegar,G.A.Michalopoulos,T.Nakamura: "Scatter factor and hepatocyte growth factor:Comparison of biologic activities and immunologic activity" Cell Growth & Differ.(1992)
[Publications] S.Osada,S.Nakashima,S.Saji,T.Nakamura and Y.Nozawa: "Hepatocyte growth factor (HGF) mediates the sustained formation of 1,2ーdiacylーglycerol via phosphatidylcholineーphosphoーlipase c in cultured rat hepatocytes." FEBS.Lett.(1992)
[Publications] K.Matsumoto,H.Tajima,M.Hamanoue,S.Kono,T.Kinoshita and T.Nakamura: "Identification and characterization of “injurin",an inducer of the gene expression of hepatocyte growth factor." Proc.Natl.Acad.Sci.USA. 89. (1992)
[Publications] M.Hamanoue,K.Kawaida,S.Takao,H.Shimazu,S.Noji,K.Matsumoto 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. (1992)
[Publications] T.Nakamura: "Structure and function of hepatocyte growth factor.Progress in Growth Factor Research,3" Pergamon Press, 67-85 (1991)
[Publications] K.Matsumoto and T.Nakamura: "Hepatocyte growth factor: molecular structure,roles in liver regeneration, and other biological functions.Critical Reviews in Oncogenesis,3" CRC Press,Inc., 27-54 (1992)

1991 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] K.Matsumoto and T.Nakamura: "Hepatocyte growth factor: molecular structure and implications for a central role in liver regeneration." Jounal of Gastroenterology and Hepatology. 6. 509-519 (1991)

[Publications] T.Seki,M.Hagiya,M.Shimonishi,T.Nakamura and S.Shimizu: "Organizaition of the human hepatocyte growth factorーencoding gene." Gene. 102. 213-219 (1991)

[Publications] T.Igawa,S.Kanda,H.Kanetake,Y.Saitoh,A.Ichihara,Y.Tomita and T.Nakamura: "Hepatocyte growth factor is a potent mitogen for cultured rabbit renal tubular epithelial cells." Biochem.Biophys.Res.Commun.174. 831-838 (1991)

[Publications] O.Asami,I.Ihara,N.Shimizu,S.Shimizu,Y.Tomita,A.Ichihara and T.Nakamura: "Purification and characterization of hepatocyte growth factor from injured liver of carbon tetrachlorideーtreated rats." J.Biochem.109. 8-13 (1991)

[Publications] I.Shimizu,A.Ichihara and T.Nakamura: "Hepatocyte growth factor in ascites from patients with cirrhosis." J.Biochem.109. 14-18 (1991)

[Publications] K.Matsumoto,H.Tajima and T.Nakamura: "Hepatocyte growth factor is a potent stimulator for human melanocyte DNA synthesis and growth." Biochem.Biophys.Res.Commun.176. 45-51 (1991)

[Publications] O.Higuchi and T.Nakamura: "Identification and change in the receptor for hepatocyte growth factoス in rat liver after partial hepatectomy or induced hepatitis." Biocem.Biophys.Res.Commun.176. 599-607 (1991)

[Publications] T.Kinoshita,S.Hirao,K.Matsumoto and T.Nakamura: "Possible endocrine control by hepatocyte growth factor of liver regeneration after partial hepatectomy." Biochem.Biophys.Res.Commun.177. 330-335 (1991)

[Publications] A.Kumatori,T.Nakamura and A.Ichihara: "Cellーdensity dependent expression of the cーmyc gene in primary cultured rat hepatocytes." Biochem.Biophys.Res.Commun.178. 480-485 (1991)

[Publications] K.Matsumoto,K.Hashimoto,K.Yoshikawa and T.Nakamura: "Marked stimulation of growth and motility of human keratinocytes by hepatocyte growth factor." Exp.Cell Res.196. 114-120 (1991)

[Publications] O.Amano,T.Tsuji,T.Nakamura and S.Iseki: "Expression of transforming growth factor bl in the submandibular gland of the rat." J.Histochem.Cytochem.39. 1707-1711 (1991)

[Publications] T.Nakamura: "Structure and function of hepatocyte growth factor." Prog.Growth Factor Res.3. 67-85 (1991)

[Publications] R.A.Furlong,T.Takehara,W.G.Taylor,T.Nakamura and J.S.Rubin: "Comparison of biological and immunoーchemical properties indicates that scatter factor and hepatocyte growth factor are indistinguishable." J.Cell Sci.100. 173-177 (1991)

[Publications] M.Nagaike,S.Hirao,H.Tajima,S.Noji,S.Taniguchi,K.Matsumoto and T.Nakamura: "Renotropic functions of hepatocyte growth factor in renal regeneration after unilateral nephrectomy." J.Biol.Chem.266. 22781-22784 (1991)

[Publications] H.Tajima,K.Matsumoto and T.Nakamura: "Hepatocyte growth factor has potent antiーproliferative activity in various tumor cell lines." FEBS Lett.291. 229-232 (1991)

[Publications] T.Takehara and T.Nakamura: "Protective effect of hepatocyte growth factor on in vitro hepatitis in primary cultured hepatocytes." Biomed.Res.12. 335-338 (1991)

[Publications] T.Konishi,T.Takehara,T.Tsuji,K.Ohsato,K.Matsumoto and T.Nakamura: "Scatter factor from human embryonic lung fibroblasts is probably identical to hepatoーcyte growth factor." Biochem.Biophys.Res.Commun.80. 765-773 (1991)

[Publications] R.Montesano,K.Matsumoto,T.Nakamura and L.Orci: "Identification of a fibroblastーderived epitheー lial morphogen as hepatocyte growth factor." Cell. 67. 901-908 (1991)

[Publications] K.Matsumoto,T.Takehara,H.Inoue,M.Hagiya,S.Shimizu and T.Nakamura: "Deletion of krngle domains or the Nーterminal hairpin structure in hepatocyte growth factor results in marked decreases in related biological activities." Biochem.Biopys.Res.Commun.181. 691-699 (1991)

[Publications] T.Mine,I.Kojima,E.Ogata and T.Nakamura: "Comparison of effects of HGF and EGF on cellular calcium in rat hepatocytes." Biochem.Biophys.Res.Commun.181. 1173-1180 (1991)

[Publications] G.Shiota,D.B.Rhoads,T.C.Wang,T.Nakamura and Emmentt V.Schmidt: "Hepatocyte growth factor inhibits growth of hepatocellular carcinoma cells." Proc.Natl.Acad.Sci.USA. 89. 373-377 (1992)

[Publications] K.Matsumoto and N.Nakamura: "Hepatocyte growth factor: molecular structure,roles in liver regeneration,and other biological functions." Crit.Rev.Oncogenesis. 3. 27-54 (1992)

[Publications] S.Ekberg,M.Luther,T.Nakamura and J.ーO.Jansson: "Growth hormone promotes early intiation of hepatocyte growth factor gene expression and DNA synthesis in rat liver after partial hepatectomy." J.Endocrinol.(1992)

[Publications] T.Kamalati,B.Thirunovukarasu,A.Wallace,N.Holder,R.Brooks,T.Nakamuta,E.Gerardi and L.Buluwela: "Downーregulation of scatter factor in MRC 5 fibroblasts by epithelialーderived cells." J.Cell Sci.101. (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. (1992)

[Publications] H.Tajima,O.Higuchi,K.Mizuno and T.Nakamura: "Tissue distribution of hepatocyte growth factor receptor and its exclusive downーregulation in a regenerating organ after the injury." J.Biochem.111. (1992)

[Publications] M.Bhargava,A.Joseph,Y.Li,S.Pang,I.Goldberg,E.Setter,M.A.Donovan,R.Zarnegar,G.A.Michalopoulos,T.Nakamura: "Scatter factor and hepatocyte growth factor:Comparison of biologic activities and immunologic activity" Cell Growth & Differ.(1992)

[Publications] S.Osada,S.Nakashima,S.Saji,T.Nakamura and Y.Nozawa: "Hepatocyte growth factor (HGF) mediates the sustained formation of 1,2ーdiacylーglycerol via phosphatidylcholineーphosphoーlipase c in cultured rat hepatocytes." FEBS.Lett.(1992)

[Publications] K.Matsumoto,H.Tajima,M.Hamanoue,S.Kono,T.Kinoshita and T.Nakamura: "Identification and characterization of “injurin",an inducer of the gene expression of hepatocyte growth factor." Proc.Natl.Acad.Sci.USA. 89. (1992)

[Publications] M.Hamanoue,K.Kawaida,S.Takao,H.Shimazu,S.Noji,K.Matsumoto 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. (1992)

[Publications] T.Nakamura: "Structure and function of hepatocyte growth factor.Progress in Growth Factor Research,3" Pergamon Press, 67-85 (1991)

[Publications] K.Matsumoto and T.Nakamura: "Hepatocyte growth factor: molecular structure,roles in liver regeneration, and other biological functions.Critical Reviews in Oncogenesis,3" CRC Press,Inc., 27-54 (1992)

中村敏一九州大学, 理学部, 教授 (00049397)