1992 年度実績報告書

癌の増殖における増殖因子の相互作用とその分子機構

研究課題

研究課題/領域番号	04151044
研究機関	広島大学
研究代表者	田原榮一広島大学, 医学部, 教授 (00033986)
研究分担者	加藤勝国立がんセンター研究所, 研究員 (50233820) 河野通明岐阜薬科大学, 助教授 (00027335) 春日雅人神戸大学, 医学部, 教授 (50161047) 伊藤文昭摂南大学, 薬学部, 教授 (80111764) 清水信義慶應大学, 医学部, 教授 (50162706)
キーワード	肝細胞増殖因子 / c-met / MAPキナーゼ / カルホスチンC / インスリンレセプター / K-sam / FGFレセプター / TGF
研究概要	ヒト胃癌細胞株における肝細胞増殖因子(HGF)の生物学的作用を解析した結果、いくつかの新しい知見がみいだされた。即ち、HGFは、パラクリン増殖因子として胃癌細胞の増殖・進展・運動及び形態形成に重要な役割を担っている可能性があり、特にc-met異常発現を示す癌細胞側の接着分子と線維芽細胞由来のHGFとの相互作用が高分化腺癌と低分化腺癌の組織発生に大きく関与している可能性が示された(田原)。また胃癌ではTGFαがc-met遺伝子の誘導を惹起させること、TGFβがHGFの細胞増殖及び運動促進を増強させることが明らかにされた(田原、伊藤)。更に、41kDa・MAPキナーゼの機能がHGFを含む増殖因子の細胞増殖促進に必須であることが示唆され(河野)、その上、HGF遺伝子導入によるマウス肝細胞あるいはMKCK細胞の形質転換が起き、その場合、HGF/c-met系のループが存在することが示された(上原、神田)。カルホスチンC(Cal-c)は、in vitroでPKCの調節ドメインに結合し光依存的に不活化するが、ヒト扁平上皮癌細胞NA及びヒト腺癌細胞A549を用いての解析により、in vivoではCal-cはPKCを阻害せずEGFレセプターリン酸化とPKCを介するシグナル伝達系を活性化しているという結論が得られた(清水)。次に、インスリンレセプターを介するシグナル伝達系では、他のチロシンキナーゼを内在するレセプターとは異なり、レセプターに直接ではなく、IRS-I蛋白にSH_2ドメインを有する蛋白が結合すると考えられ、一方、EGFレセプターの場合には、GAP及びPI_3キナーゼはその伝達物質としての役割は小さいと考えられた(春日)。サイズの異なるK-sam mRNAの構造解析より、K-sam遺伝子はFGFレセプターファミリーに属する膜貫通型レセプターのみならず分泌型レセプターをコードしていることが明らかにされた(加藤)。

研究成果
(20件)

すべてその他

すべて文献書誌 (20件)

[文献書誌] Kitadai Y: "GC factor represses transcription of several growth factor/receptor genes and causes growth inhibition of human gastric carcinoma cell lines." Cell Growth & Dfferentiation. 4. (1993)
[文献書誌] Ito M: "Growth inhibition of transforming growth factor β on human gastric carcinoma cells:receptor and postreceptor sinaling." Cancer Research. 52. 295-300 (1992)
[文献書誌] Saeki T: "Differential immunohistichemical detection of amphiregulin and cripto in human normal colon and colorectral tumors." Cancer Research. 52. 3467-3473 (1992)
[文献書誌] Kameda T: "Tyrosine kinase activity of epidermal growth factor receptor in human gastric carcinomas." Path.Res.Pract.188. 37-43 (1992)
[文献書誌] Kuniyasu H: "Frequent amplification of the c-met gene in scirrhous type stomach cancer." Biochem.Biophys.Res.Commun.189. 227-232 (1992)
[文献書誌] Kitadai Y: "The level of a trascription factor Spl in correlated with the expression of EGF receptor in human gastric carcinomas." Biochem.Biophys.Res.Commun.189. 1342-1348 (1992)
[文献書誌] Kohno M: "Mitogen-induced tyrosine phosphorylation of 41 kDa and 43 kDa proteins.-Potential role in integrating multiple mitogenic signalling pathways." Biochem.J.287. 917-924 (1992)
[文献書誌] Tsuji K: "Inhibitory effect of taxol,a microtubule stabilizing agent,on induction of DNA synthesis is dependent cell lines and growth factors." Cell Struct.Funct.17. 139-144 (1992)
[文献書誌] Tsuda H: "Different pattern of chromosomal allele loss in multiple hepatocellulat carcinomas as evidence of their multifocal origin." Cancer Research. 52. 1504-1509 (1992)
[文献書誌] Tsuda H: "Prognostic factors post-recurrent breast caner:univariate and multivariate analyses including histologic grade and amplification of c-erbB-2proto-oncogene." Jpn.J.Clin.Oncol.22. 244-250 (1992)
[文献書誌] Katoh.M: "K-sam gene encodes secreted as well as transmembrane receptor tyrosine kinase." Proc.Natl.Acad.Sci.USA. 89. 2960-2964 (1992)
[文献書誌] Uehara Y: "Expression of a human hepatocyte growth factor/scatter factor cDNA in MDCK epithelial cells influences cell morphology,motility and anchorage-independent growth." J.Cell Biology.117. 889-894 (1992)
[文献書誌] Sakai K: "Molecular cloning and chromosomal mapping of a cDNA encoding human 80K-L protein: major substrate for protein kinase C." Genomics. 14. 175-178 (1992)
[文献書誌] Yonezawa K: "In vitro association of phosphatidylinositol 3-kinase activity with the activated insulin receptor tyrosine kinase." J.Biol.Chem.267. 440-446 (1992)
[文献書誌] Ando A: "Enhanced insulin-induced mitogenesis and mitogen-activated protein kinase activities in mutant insulin receptors with substitution of two COOH-terminal tyrosine autophosphorylation sites by phenylalanine." J.Biol.Chem.267. 12788-12796 (1992)
[文献書誌] Chatani Y: "Mitogen-induced tyrosine-phosphorylated 41-and 43-kDa proteins are family members of extracellular signal-regulated kinases/microguble-associated protein 2 kinases." J.Biol.Chem.267. 9911-9916 (1992)
[文献書誌] Chatani Y: "Hepatocyte growth factor rapidly induced the tyrosine phosphorylation of 41-kDa adn 43-kDa proteins mouse keratinocytes." Biochem.Biophys.Res.Commu.185. 860-866 (1992)
[文献書誌] Okigaki M: "Functional characterization of human hepatocyte growth factor mutans obtained by deletion of structural domains." Biochemistry. 31. 9555-9561 (1992)
[文献書誌] Yasui W: "Surgical Gynecologic Oncology Edited by E.Burghardt" Thieme Medical Publishers,Inc.New York, 729 (1993)
[文献書誌] Shimizu N: "Lung Cancer Differentiation Edited by S.E.Bernal and P.J.Hesketh" Marcel Dkker,Inc., 158 (1992)

1992 年度 実績報告書

癌の増殖における増殖因子の相互作用とその分子機構

研究代表者

田原 榮一 広島大学, 医学部, 教授 (00033986)

研究成果

[文献書誌] Kitadai Y: "GC factor represses transcription of several growth factor/receptor genes and causes growth inhibition of human gastric carcinoma cell lines." Cell Growth & Dfferentiation. 4. (1993)

[文献書誌] Ito M: "Growth inhibition of transforming growth factor β on human gastric carcinoma cells:receptor and postreceptor sinaling." Cancer Research. 52. 295-300 (1992)

[文献書誌] Saeki T: "Differential immunohistichemical detection of amphiregulin and cripto in human normal colon and colorectral tumors." Cancer Research. 52. 3467-3473 (1992)

[文献書誌] Kameda T: "Tyrosine kinase activity of epidermal growth factor receptor in human gastric carcinomas." Path.Res.Pract.188. 37-43 (1992)

[文献書誌] Kuniyasu H: "Frequent amplification of the c-met gene in scirrhous type stomach cancer." Biochem.Biophys.Res.Commun.189. 227-232 (1992)

[文献書誌] Kitadai Y: "The level of a trascription factor Spl in correlated with the expression of EGF receptor in human gastric carcinomas." Biochem.Biophys.Res.Commun.189. 1342-1348 (1992)

[文献書誌] Kohno M: "Mitogen-induced tyrosine phosphorylation of 41 kDa and 43 kDa proteins.-Potential role in integrating multiple mitogenic signalling pathways." Biochem.J.287. 917-924 (1992)

[文献書誌] Tsuji K: "Inhibitory effect of taxol,a microtubule stabilizing agent,on induction of DNA synthesis is dependent cell lines and growth factors." Cell Struct.Funct.17. 139-144 (1992)

[文献書誌] Tsuda H: "Different pattern of chromosomal allele loss in multiple hepatocellulat carcinomas as evidence of their multifocal origin." Cancer Research. 52. 1504-1509 (1992)

[文献書誌] Tsuda H: "Prognostic factors post-recurrent breast caner:univariate and multivariate analyses including histologic grade and amplification of c-erbB-2proto-oncogene." Jpn.J.Clin.Oncol.22. 244-250 (1992)

[文献書誌] Katoh.M: "K-sam gene encodes secreted as well as transmembrane receptor tyrosine kinase." Proc.Natl.Acad.Sci.USA. 89. 2960-2964 (1992)

[文献書誌] Uehara Y: "Expression of a human hepatocyte growth factor/scatter factor cDNA in MDCK epithelial cells influences cell morphology,motility and anchorage-independent growth." J.Cell Biology.117. 889-894 (1992)

[文献書誌] Sakai K: "Molecular cloning and chromosomal mapping of a cDNA encoding human 80K-L protein: major substrate for protein kinase C." Genomics. 14. 175-178 (1992)

[文献書誌] Yonezawa K: "In vitro association of phosphatidylinositol 3-kinase activity with the activated insulin receptor tyrosine kinase." J.Biol.Chem.267. 440-446 (1992)

[文献書誌] Ando A: "Enhanced insulin-induced mitogenesis and mitogen-activated protein kinase activities in mutant insulin receptors with substitution of two COOH-terminal tyrosine autophosphorylation sites by phenylalanine." J.Biol.Chem.267. 12788-12796 (1992)

[文献書誌] Chatani Y: "Mitogen-induced tyrosine-phosphorylated 41-and 43-kDa proteins are family members of extracellular signal-regulated kinases/microguble-associated protein 2 kinases." J.Biol.Chem.267. 9911-9916 (1992)

[文献書誌] Chatani Y: "Hepatocyte growth factor rapidly induced the tyrosine phosphorylation of 41-kDa adn 43-kDa proteins mouse keratinocytes." Biochem.Biophys.Res.Commu.185. 860-866 (1992)

[文献書誌] Okigaki M: "Functional characterization of human hepatocyte growth factor mutans obtained by deletion of structural domains." Biochemistry. 31. 9555-9561 (1992)

[文献書誌] Yasui W: "Surgical Gynecologic Oncology Edited by E.Burghardt" Thieme Medical Publishers,Inc.New York, 729 (1993)

[文献書誌] Shimizu N: "Lung Cancer Differentiation Edited by S.E.Bernal and P.J.Hesketh" Marcel Dkker,Inc., 158 (1992)

1992 年度実績報告書

田原榮一広島大学, 医学部, 教授 (00033986)