1992 Fiscal Year Annual Research Report

肝発癌過程のマーカー酵素の特異的発現機構と機能の解明

Research Project

Project/Area Number	04151005
Research Institution	Tottori University
Principal Investigator	遠藤英也鳥取大学, 医学部, 教授 (40037320)
Co-Investigator(Kenkyū-buntansha)	貝淵弘三神戸大学, 医学部, 助教授 (00169377) 宮城妙子東北大学, 抗酸菌病研究所, 助教授 (50006110) 菊池九二三北海道大学, 免疫科学研究所, 教授 (20006117) 村松正實埼玉医科大学, 教授 (10035454) 佐藤公彦弘前大学, 医学部, 助教授 (70003655)
Keywords	肝発癌 / マーカー酵素 / グルタチオンS-トランスフェラーゼ / 転写調節因子 / 癌遺伝子 / Gタンパク / プロティンホスファターゼ / シアリダーゼ
Research Abstract	今年度の主要な研究成果は以下の通りである。 1)GST-P遺伝子の上流とCAT遺伝子をつなぎ、トランスジェニックラットを作出し、肝前癌誘発実験から、未同定の癌遺伝子とGST-P遺伝子とが、同じトランス作用因子を共有する可能性が示唆された。2)癌化に伴うラット肝カタラーゼ活性の減少に関し、ヌードマウスへの種々の腫瘍移植に伴う肝mRNAの共通の低下を認め、run-on実験から転写レベルの調節抑制が伴明した。3)再生肝術後経過におけるプロティンホスファターゼPP1とPP2Aの変化を調べ、mRNAと蛋白(活性)レベルの挙動は異なること、およびPP1のG1-S期移行における重要性が示唆された。4)ラット骨格筋の細胞質シアリダーゼをクローニングし、379アミノ酸をコードするcDNAを得た。哺乳動物では最初である。5)ras p21がMAPキナーゼ・キナーゼを活性化するツメガエル卵の無細胞系を開発し、ras p21の標的とみなされる蛋白因子(REKS)を部分精製した。6)マウスHepa-1細胞BP耐性の2変異株のP-450IA1cDNAクローニングを行い、アミノ酸置換を確認した。同遺伝子の誘導発現にAh-リセプターを介さない経路の存在が示唆された。7)上皮性卵巣癌などのマーカー酵素、Mn-SODの血中放出には、TNFやIL-1などのサイトカイン刺激により腫瘍の血管内皮細胞にMn-SODが誘導され、同時に細胞の壊死を伴う機序が、培養実験より示唆された。8)c-Junは、免疫組織化学的にマウス前癌病巣の最良のマーカーであった。肝発癌のマーカー酵素、GST-P、PKM、カタラーゼなどの発現調節機構を究明するために、これらの遺伝子のシスおよびトランス作用因子を検討した。また生理機能の検討も含め、癌性変化を示す酵素cDNAクローニングも行った。単一の遺伝子にも複数の制御領域、制御因子が存在し、共通の因子による遺伝子の発現制御がなされていることも明らかになった。それらの全容の解明は容易でないが着実に研究が進展しつつある。

Research Products

(37 results)

All Other

All Publications (37 results)

[Publications] Ito Nobuyuki: "Pathological markers for non-genotoxic agent-associated carcinogenesis" Toxicology Letters. 64/65. 613-620 (1992)
[Publications] Ando Satoshi: "Post-translational processing of ras p21s is important both for their interaction with the GDP/GTP exchange proteins and for their activation of NADPH oxidase" Journal of Biological Chemistry,in press. (1992)
[Publications] Ito Takahito: "The post-translational processing of ras p21 is critical for its stimulation of Mitogen-activated protein (MAP)kinase" Journal of Biological Chemistry,in press. (1992)
[Publications] Itoh Takahito: "A novel protein factor for ras p21-dependent activation of Mitogen-activated protein kinase" Proceedings of the National Academy of Science U.S.A,in press. (1992)
[Publications] Hiraoka Kunihiko: "Both stimulatory and inhibitory GDP/GTP exchange proteins,smg GDS and rho GDI,are active on multiple small GTP-binding proteins" Biochemical and Biophysical Research Communication. 182. 921-930 (1992)
[Publications] Kawamura Naohisa: "High levels of Mn-superoxide dismutase in serum of patients with neuroblastoma and in neuroblastoma cell lines" Free Radical Biology and Medicine. 12. 281-286 (1992)
[Publications] Sakai Masaharu: "Suppression of glutathione transferase P expression by glucocorticoid" Biochemical and Biophysical Research Communication. 187. 976-983 (1992)
[Publications] Mitchell B.Diccianni: "The dyad palindromic glutathione transferase P enhancer binds multiple factors including AP1" Nucleic Acids Research. 20. 5153-5158 (1992)
[Publications] Morimura Shigeru: "Analysis of glutathione transferase P gene regulation with liver cells in primary culture" Cell Growth & Differentiation. 3. 685-691 (1992)
[Publications] Sato Kenzo: "Negative regulation of catalase gene expression in hepatoma cells" Molecular and Cellular Biology. 12. 2525-2533 (1992)
[Publications] Yamaguchi Yumi: "Depression of catalase gene expression in the liver of tumor bearing nude mouse" Biochemical and Biophysical Research Communication. 189. 1084-1089 (1992)
[Publications] Roland Netzker: "Cell cycle-associated expression of M2-type isozyme of pyruvate kinase in proliferating rat thymocytes" Journal of Biological Chemistry. 267. 6421-6424 (1992)
[Publications] Nishiur Tetsuo: "Elevated serum manganese superoxide dismutase in acute leukemias" Cancer Letters. 62. 211-215 (1992)
[Publications] Ono Minoru: "Induction of Mn-superoxide dismutase by tumor necrosis factor,interleukin-1 and interleukin-6 in human hepatoma cells" Biochemical and Biophysical Research Communication. 182. 1100-1107 (1992)
[Publications] Satoh Shoji: "Distribution of manganese superoxide dismutase in rat stomach:Application of triton X-100 and suppression of endogenous streptavidin binding activity" Journal of Histochemistry and Cytochemistry. 40. 1157-1163 (1992)
[Publications] Suzuki Keiichiro: "Elevation of immunoreactive serum Mn-superoxide dismutase in patients with acute myocardial infarction" Free Radical Biology and Medicine. 15. 325-334 (1992)
[Publications] Taniguchi Naoyuki: "Clinical significance of superoxide dismutase:Changes in aging,diabetes,ischemia,and cancer" Advances in Clinical Chemistry. 29. 1-59 (1992)
[Publications] Nakata Toshiyuki: "High expression of Mn-superoxide dismutase in 7,12-dimethylbenz(a)anthracene-induced ovarian cancer and increased serum levels in the tumor-bearing rats" Carcinogenesis. 13. 1941-1943 (1992)
[Publications] Kitamura Kazuki: "mRNA levels of catalytic subunits of protein phosphatases 1,2A,and 2C in hepatocarcinogenesis" Japanese Journal of Cancer Research. 83. 66-71 (1992)
[Publications] Kakinoki Yasutaka: "Gene expressions and activities of protein phosphatase PP1 and PP2 in rat liver regeneration after partial hepatectomy" Biochemical and Biophysical Research Communication. 185. 291-297 (1992)
[Publications] Nakamura Koji: "Cell cycle dependent gene expressions and activities of protein phosphatases PP1 and PP2A in mouse NIH3T3 fibroblasts" Biochemical and Biophysical Research Communication. 187. 507-514 (1992)
[Publications] Fujioka Hiroyuki: "Transforming and c-fos promoter/enhancer-stimulating activities of a stimulatory GDP/GTP exchange protein for small GTP-binding proteins" Journal of Biological Chemistry. 267. 926-930 (1992)
[Publications] Hirata Ken-ichi: "Involvement of rho p21 in the GTP-enhanced calcium ion sensitivity of smooth muscle" Journal of Biological Chemistry. 267. 8719-8722 (1992)
[Publications] Mizuno Takakazu: "Regulation of the superoxide-generationg NADPH oxidase by stimulatory and inhibitory GDP/GTP exchange protein for small G proteins" Journal of Biological Chemistry. 276. 10215-10218 (1992)
[Publications] Shirataki Hiromichi: "Possible target for smg-25A/rab3A small GTP-binding protein" Journal of Biological Chemistry. 267. 10946-10949 (1992)
[Publications] Horiuchi Hisanori: "The post-translational processing of ras p21 is critical for its stimulation of yeast adenylate cyclase in a cell-free system" Molecular and Cellular Biology. 12. 4515-4520 (1992)
[Publications] Kikuchi Akira: "Molecular cloning of the human cDNA for a stimulatory GDP/GTP exchange protein for c-Ki-ras p21 and smg p21." Oncogene. 7. 289-293 (1992)
[Publications] Adachi Masashi: "Induction of smg p21/rap1A p21/Krev-1 p21 gene expression during the phorbol ester-induced differentiation of a human megakaryocytic leukemia cell line" Oncogene. 7. 323-329 (1992)
[Publications] Sakoda Tsuyoshi: "Inhibition by smg/rap1/Krev-1 p21s of the ras p21-stimulated c-fos promoter/enhancer in NIH/3T3 cells" Oncogene. 7. 1705-1711 (1992)
[Publications] Miura Yasushi: "Phosphorylation of smg p21B/rap1B p21 by cyclic GMP-dependent protein kinase" FEBS Letters. 297. 171-174 (1992)
[Publications] Ueno Yoshio: "Enhancement of GST-P positive liver foci development by nivalenol,a trichothecene mycotoxin" Carcinogenesis. 13. 787-791 (1992)
[Publications] Hasegawa Ryohei: "Suppression of diethyl-nitrosamine-initiated preneoplastic foci development in the rat liver by combined administration of four antioxidants ot low doses" Japanese Journal of Cancer Research. 83. 431-437 (1992)
[Publications] Ogawa Kumiko: "Dose response study of N-nitrosodiethanolamine for initiation of rat hepatocarcinogenesis" Teratogenesis Carcinogenesis & Mutagenesis. 11. 245-250 (1992)
[Publications] Hasegawa Ryohei: "Dose-dependent formation of preneoplastic foci and DNA adducts in rat liver with 2-amino-3-methyl-pH-pyrido(2,3-b)indole(MeAaC)and 2-amino-1-methyl-6-phenylimidazo(4,5-pyridine (PhIP)" Carcinogenesis. 13. 1427-1431 (1992)
[Publications] Hasegawa Ryohei: "Liver medium-term bioassay in rats for screening of carcinogens and modifying factors in hepatocarcinogenesis" Food Chemical Toxicology. 11. 979-992 (1992)
[Publications] Hasegawa Ryohei: "3,2'-Dimethyl-4-aminobiphenyl-induced gallbladder carcinogenesis and effects of ethinyl estradiol in hamsters" Japanese Journal of Cancer Research. 83. 1286-1292 (1992)
[Publications] Yokoyama Yoshihito: "Loss of peroxisomal enzyme expression in preneoplastic and neoplastic lesions induced by peroxisome proliferators in rat livers" Carcinogenesis. 13. 265-269 (1992)

1992 Fiscal Year Annual Research Report

肝発癌過程のマーカー酵素の特異的発現機構と機能の解明

Principal Investigator

遠藤 英也 鳥取大学, 医学部, 教授 (40037320)

Research Products

[Publications] Ito Nobuyuki: "Pathological markers for non-genotoxic agent-associated carcinogenesis" Toxicology Letters. 64/65. 613-620 (1992)

[Publications] Ando Satoshi: "Post-translational processing of ras p21s is important both for their interaction with the GDP/GTP exchange proteins and for their activation of NADPH oxidase" Journal of Biological Chemistry,in press. (1992)

[Publications] Ito Takahito: "The post-translational processing of ras p21 is critical for its stimulation of Mitogen-activated protein (MAP)kinase" Journal of Biological Chemistry,in press. (1992)

[Publications] Itoh Takahito: "A novel protein factor for ras p21-dependent activation of Mitogen-activated protein kinase" Proceedings of the National Academy of Science U.S.A,in press. (1992)

[Publications] Hiraoka Kunihiko: "Both stimulatory and inhibitory GDP/GTP exchange proteins,smg GDS and rho GDI,are active on multiple small GTP-binding proteins" Biochemical and Biophysical Research Communication. 182. 921-930 (1992)

[Publications] Kawamura Naohisa: "High levels of Mn-superoxide dismutase in serum of patients with neuroblastoma and in neuroblastoma cell lines" Free Radical Biology and Medicine. 12. 281-286 (1992)

[Publications] Sakai Masaharu: "Suppression of glutathione transferase P expression by glucocorticoid" Biochemical and Biophysical Research Communication. 187. 976-983 (1992)

[Publications] Mitchell B.Diccianni: "The dyad palindromic glutathione transferase P enhancer binds multiple factors including AP1" Nucleic Acids Research. 20. 5153-5158 (1992)

[Publications] Morimura Shigeru: "Analysis of glutathione transferase P gene regulation with liver cells in primary culture" Cell Growth & Differentiation. 3. 685-691 (1992)

[Publications] Sato Kenzo: "Negative regulation of catalase gene expression in hepatoma cells" Molecular and Cellular Biology. 12. 2525-2533 (1992)

[Publications] Yamaguchi Yumi: "Depression of catalase gene expression in the liver of tumor bearing nude mouse" Biochemical and Biophysical Research Communication. 189. 1084-1089 (1992)

[Publications] Roland Netzker: "Cell cycle-associated expression of M2-type isozyme of pyruvate kinase in proliferating rat thymocytes" Journal of Biological Chemistry. 267. 6421-6424 (1992)

[Publications] Nishiur Tetsuo: "Elevated serum manganese superoxide dismutase in acute leukemias" Cancer Letters. 62. 211-215 (1992)

[Publications] Ono Minoru: "Induction of Mn-superoxide dismutase by tumor necrosis factor,interleukin-1 and interleukin-6 in human hepatoma cells" Biochemical and Biophysical Research Communication. 182. 1100-1107 (1992)

[Publications] Satoh Shoji: "Distribution of manganese superoxide dismutase in rat stomach:Application of triton X-100 and suppression of endogenous streptavidin binding activity" Journal of Histochemistry and Cytochemistry. 40. 1157-1163 (1992)

[Publications] Suzuki Keiichiro: "Elevation of immunoreactive serum Mn-superoxide dismutase in patients with acute myocardial infarction" Free Radical Biology and Medicine. 15. 325-334 (1992)

[Publications] Taniguchi Naoyuki: "Clinical significance of superoxide dismutase:Changes in aging,diabetes,ischemia,and cancer" Advances in Clinical Chemistry. 29. 1-59 (1992)

[Publications] Nakata Toshiyuki: "High expression of Mn-superoxide dismutase in 7,12-dimethylbenz(a)anthracene-induced ovarian cancer and increased serum levels in the tumor-bearing rats" Carcinogenesis. 13. 1941-1943 (1992)

[Publications] Kitamura Kazuki: "mRNA levels of catalytic subunits of protein phosphatases 1,2A,and 2C in hepatocarcinogenesis" Japanese Journal of Cancer Research. 83. 66-71 (1992)

[Publications] Kakinoki Yasutaka: "Gene expressions and activities of protein phosphatase PP1 and PP2 in rat liver regeneration after partial hepatectomy" Biochemical and Biophysical Research Communication. 185. 291-297 (1992)

[Publications] Nakamura Koji: "Cell cycle dependent gene expressions and activities of protein phosphatases PP1 and PP2A in mouse NIH3T3 fibroblasts" Biochemical and Biophysical Research Communication. 187. 507-514 (1992)

[Publications] Fujioka Hiroyuki: "Transforming and c-fos promoter/enhancer-stimulating activities of a stimulatory GDP/GTP exchange protein for small GTP-binding proteins" Journal of Biological Chemistry. 267. 926-930 (1992)

[Publications] Hirata Ken-ichi: "Involvement of rho p21 in the GTP-enhanced calcium ion sensitivity of smooth muscle" Journal of Biological Chemistry. 267. 8719-8722 (1992)

[Publications] Mizuno Takakazu: "Regulation of the superoxide-generationg NADPH oxidase by stimulatory and inhibitory GDP/GTP exchange protein for small G proteins" Journal of Biological Chemistry. 276. 10215-10218 (1992)

[Publications] Shirataki Hiromichi: "Possible target for smg-25A/rab3A small GTP-binding protein" Journal of Biological Chemistry. 267. 10946-10949 (1992)

[Publications] Horiuchi Hisanori: "The post-translational processing of ras p21 is critical for its stimulation of yeast adenylate cyclase in a cell-free system" Molecular and Cellular Biology. 12. 4515-4520 (1992)

[Publications] Kikuchi Akira: "Molecular cloning of the human cDNA for a stimulatory GDP/GTP exchange protein for c-Ki-ras p21 and smg p21." Oncogene. 7. 289-293 (1992)

[Publications] Adachi Masashi: "Induction of smg p21/rap1A p21/Krev-1 p21 gene expression during the phorbol ester-induced differentiation of a human megakaryocytic leukemia cell line" Oncogene. 7. 323-329 (1992)

[Publications] Sakoda Tsuyoshi: "Inhibition by smg/rap1/Krev-1 p21s of the ras p21-stimulated c-fos promoter/enhancer in NIH/3T3 cells" Oncogene. 7. 1705-1711 (1992)

[Publications] Miura Yasushi: "Phosphorylation of smg p21B/rap1B p21 by cyclic GMP-dependent protein kinase" FEBS Letters. 297. 171-174 (1992)

[Publications] Ueno Yoshio: "Enhancement of GST-P positive liver foci development by nivalenol,a trichothecene mycotoxin" Carcinogenesis. 13. 787-791 (1992)

[Publications] Hasegawa Ryohei: "Suppression of diethyl-nitrosamine-initiated preneoplastic foci development in the rat liver by combined administration of four antioxidants ot low doses" Japanese Journal of Cancer Research. 83. 431-437 (1992)

[Publications] Ogawa Kumiko: "Dose response study of N-nitrosodiethanolamine for initiation of rat hepatocarcinogenesis" Teratogenesis Carcinogenesis & Mutagenesis. 11. 245-250 (1992)

[Publications] Hasegawa Ryohei: "Dose-dependent formation of preneoplastic foci and DNA adducts in rat liver with 2-amino-3-methyl-pH-pyrido(2,3-b)indole(MeAaC)and 2-amino-1-methyl-6-phenylimidazo(4,5-pyridine (PhIP)" Carcinogenesis. 13. 1427-1431 (1992)

[Publications] Hasegawa Ryohei: "Liver medium-term bioassay in rats for screening of carcinogens and modifying factors in hepatocarcinogenesis" Food Chemical Toxicology. 11. 979-992 (1992)

[Publications] Hasegawa Ryohei: "3,2'-Dimethyl-4-aminobiphenyl-induced gallbladder carcinogenesis and effects of ethinyl estradiol in hamsters" Japanese Journal of Cancer Research. 83. 1286-1292 (1992)

[Publications] Yokoyama Yoshihito: "Loss of peroxisomal enzyme expression in preneoplastic and neoplastic lesions induced by peroxisome proliferators in rat livers" Carcinogenesis. 13. 265-269 (1992)

遠藤英也鳥取大学, 医学部, 教授 (40037320)