癌の増殖における増殖因子の相互作用とその分子機構

1991 Fiscal Year Annual Research Report

• Project/Area Number: 03151043
• Research Institution: Hiroshima University
• Principal Investigator: 田原 榮一 広島大学, 医学部, 教授 (00033986)
• Co-Investigator(Kenkyū-buntansha): 豊島 秀男 東京大学, 医学部, 助手 (20197966) ; 河野 通明 岐阜薬科大学, 薬学部, 助教授 (00027335) ; 伊藤 文昭 摂南大学, 薬学部, 教授 (80111764) ; 春日 雅人 神戸大学, 医学部, 教授 (50161047) ; 清水 信義 慶應義塾大学, 医学部, 教授 (50162706)
• Keywords: 増殖因子 / GCF / 転写因子 / FGF / cーmet / cripto / PDーECGF / インスリン受容体 / チロシンキナ-ゼ

Research Abstract

GCF(GC rich配列結合蛋白)は、異なった複数の増殖因子・受容体(TGFα,EGF受容体,ERBB2,FGF受容体ー1)遺伝子プロモ-タ-に結合し、それらの遺伝子発現を抑制する負の共通した転写因子であることが実証され、更に、GCF遺伝子導入胃癌細胞株では、TGFα・ERF受容体の減少とともに、癌細胞自己増殖の著しい減少がin vitro,in vivoで確認された(田原)。次に、ヒト肝細胞増殖因子(HGF)遺伝子は染色体7q21.1に位置すること(清水)、また同じ7qに存在するHGF受容受体遺伝子cーmetの異常(欠失、増幅)は胃癌に頻発すること、cーmet mRNA 6.0kb transcriptは胃癌細胞のみに発現して、その進展・転移とよく相関することなどか明らかにされた(田原)。又、HGFによって胃癌細胞株の増殖促進、cーmet蛋白の自己リン酸化、プログタグランジン産生などが惹起され(田原、伊藤)、更に種々のペプチド増殖因子によって誘導される細胞質41k,43k蛋白質チロシンリン酸化をもHGFによって起きることが示された(河野)。新しいEGF関連遺伝子、criptoの臓器別発現では、甲状腺、腸、腎に高く、腫瘍では大腸癌、高分化胃癌に特徴的に高い発現を示し、その進展と相関することが明らかにされた。又、血小板由来血管内皮細胞増殖因子(PDーECGF)は、ヒト肝実質細胞と肝細胞癌に特異的に発現しており、肝実質細胞の自己増殖因子である可能性が示唆された(豊島)。インスリン受容体を介するシグナル伝達系に関しては、siteーdirected mutagenesisの手法を用いて、各種の変異受容体を作製してその機能を検討した結果、インスリン受容体のレベルで各種インスリン作用が分岐している可能性が示され(春日)、更にヒトKB細胞ではインスリンがEGF依存性増殖を抑制し、一方、TGFβ1もEGF依存性増殖を阻害するが、インスリン依存性増殖には大きな影響を及ぼさないことが明らかにされた(天野)。

Research Products

• [Publications] Kuniyasu H: "Expression of cripto,a novel gene of the epidermal growth factor family,in human gastrointestinal carcinomas." Japanese Journal of Cancer Research. 82. 969-973 (1991)
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• [Publications] Amano F: "Isolation and characterization of a mutant cel line defective in maturation and processing of EGF receptors from KB mutant cells resistant of EGF-Pseudomonas exotoxin conjugates."
• [Publications] Sasaki A: "Application of lectin and B-lympho-cytes-specific monoclonal antibodies for the demonstration of human microglia in formalin-fixed,paraffin-embedded brain tissue." Virchows Archiv A Pathol Anat.419. 291-299 (1991)
• [Publications] Moses H: "Identification of an interferon-γ-responsive element of a class II major histocompatibility gene in rat type 1 astrocytes." J.Neuroimmunol.35. 273-278 (1991)
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• [Publications] Nakayama A: "Immunocytochemical observation of paraquat-Induced alveolitis:with special reference to class II MHC antigens." Virchows Arch B.
• [Publications] Kasayama S: "Heparin inhibits autocrine stimulation but not fibroblast growth factor stimulation of cell proliferation of androgen-responsive Shionogi carcinoma." J.Cell Physiol.148. 260-266 (1991)
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• [Publications] Saito H: "Up-regulation of fibroblast growth factor (FGF) receptor mRNA levels by basic FGF or testosterone in androgen-sensitive mouse mammary tumor cells." Biochem.Biophys.Res.Commun.174. 136-141 (1991)
• [Publications] Motozaki T: "Cholecystokinin inhibits phosphatidylcholine synthesis via CA^<2+>-calmodulin-dependent pathway in isolated rat pancreatic acinti:A possible mechanism for diacylgycerol accumulation." J.Biol.Chem.(1991)
• [Publications] Tobe K: "Insulin and 12-o-tetradecanoyl phorbol 13-acetate (TPA) activation of two immunologically distinct MBP/MAP2 kinases via de novo phosphorylation of threonine and tyrosine residues." J.Biol.Chem.(1991)
• [Publications] Tsuji K: "Dual effect of protein kinase C on the induction of DNA synthesis by colcemid in GO-arrested human diploid fibroblasts." Cell Struct.Funct.16. 73-80 (1991)
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• [Publications] Miyake E: "A cell cycle ts mutant,tsJT16,is defective in p70 synthesis through protein kinase C-dependent and -independent pathways." Cell Struct.Funct.16. 315-321 (1991)
• [Publications] Kihana T: "Point mutation of c-Ki-ras oncogene in gastric adenoma and adenocarcinoma with tubular differentiation." Jpn.J.Cancer Res.82. 308-314 (1991)
• [Publications] Fukuyama R: "Detection of EGF receptors and E-cadherins in the basolateral membrane of A431 cells by laser scanning fluorescence microscopy." Japanese Journal of Cancer Research. 82. 8-11 (1991)
• [Publications] Fukuyama R: "Expression of epidermal growth factor (EGF) and EGF receptor in human tissues." J.Exp.Zool.258. 336-343 (1991)
• [Publications] Fukuyama R: "Regional localization of the hepatocyte growth factor (HGF) gene to human chromosome 7 band q21.1." Genomics. 11. 410-415 (1991)
• [Publications] Hori T: "Prostaglandins antagonize fibroblast proliferation stimulated by tumor necrosis factor." Biochem.Biophys.Acta.174. 758-766 (1991)
• [Publications] Hayakawa M: "Solubilization of human placental tumor necrosis factor receptors as a complex with a guanine nucleotide-binding protein." Arch.Biochem.Biophys.286. 323-329 (1991)
• [Publications] Hayakawa M: "Involvement of prostaglandin-producing pathway in the cytotoxic action of tumor necrosis factor." Cell Struc.Funct.16. 333-340 (1991)
• [Publications] Kouhara H: "Expression cDNA cloning of fibroblast growth factor (FGF) receptor in mouse breast cancer cells." Biochem.Biophys.Res.Commun.176. 31-37 (1991)
• [Publications] Akatsuka A: "Electoron microscopic identification of the intracellular secretion pathway of human G-CSF in a human tumor cell line:A comparative study with a chinese hamster ovary cell line (IAI-7) transfected with human G-CSF cDNA." Experimental Hematology. 19. 768-772 (1991)
• [Publications] Sato M: "Control Cell Growth and Gene Expression." Japan Sci.Soc.Press Tokyo/Springer-Verlag,Berlin, 20 (1991)
• [Publications] 田原 榮一: "現代病理学大系17B" 中山書店, 40 (1991)