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1996 Fiscal Year Final Research Report Summary

Initiation and Its Inhibition by Carcinogenes in transgenic Mice Carried with MGMT Gene.

Research Project

Project/Area Number 05404023
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Experimental pathology
Research InstitutionUniversity of Tokyo

Principal Investigator

ISHIKAWA Takatoshi  University of Tokyo, Department of Pathology, Faculty of Medicine, Professor, 医学部, 教授 (30085633)

Co-Investigator(Kenkyū-buntansha) NAKATSURU Yoko  University of Tokyo, Department of Pathology, Faculty of Medicine, Assistant, 医学部, 助手 (00237314)
ODA Hideaki  University of Tokyo, Department of Pathology, Faculty of Medicine, Associate Pro, 医学部, 助教授 (40214142)
Project Period (FY) 1993 – 1996
KeywordsMGMT / Transgenic mice / O^6-methylguanine / Liver carcinogenesis / Nitrosamine / 突然変異 / O^6-メチルグアニン / がん遺伝子
Research Abstract

The E.coli ada gene encodes O^6-methylguanine DNA methyltransferase (MGMT) which repairs the methylation of guanine at the O^6 position in DNA.After recombination with a Chinese hamster metallothionein I gene promoter, the ada gene was micro injected into C3H/HeN mouse Zygotes. Eventually, transgenic mice containing the ada fusion DNA were generated. The integrated ada DNA complex was transmitted to the progeny in a mode conforming to tandem integration a single chromosome site, and homozygotes were also obtained from an inter-transgenic mouse cross. RNA transcripts of the chimeric ada gene were identified in the livers of these transgenic mice using Northern blot analysis. The ada gene product was detected in the liver from ada mice by immunoblot analysis. Because the ada gene was expressed under the control of the metallothionein promoter, the MGMT activity of the liver from transgenic homozygote showed approximately 3 times the control activity, a marked increase of up to about 8 times the non-transgenic control levels being observed 10 h after zinc treatment. Using ada mice and nontransgenic control mice, ada mouse was resistant to tumorigenesis when treated with liver carcinogens, dimethylnitrosamine or diethylnitrosamine. Transgenic mice expressing ada gene derived from C3H/HeN mouse, C3H mouse strain is generally known to develop spontaneous liver tumors at high incidence in later life. We further compared the incidence of spontaneous liver tumors between ada mice and nontransgenic control mice. In results, both groups developed liver tumors at the same incidence (48%). However, the histological examination showed the incidence of hepatocellular carcinoma in ada mouse was significantly lower than in nontransgenic mouse. These observations suggest that MGMT may also protect mice from tumor progression.

  • Research Products

    (35 results)

All Other

All Publications (35 results)

  • [Publications] Qin,X.,Ishikawa,T.et al.: "Detection of ultraviolet-photoproducts in mouse skin exposed natural sunlight." Jpn.J.Cancer Res.87. 685-690 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Oda,H.,Ishikawa,T.et al.: "Somatic mutations of the APC gene in sporadic hepatoblastomas." Cancer Res.56. 3320-3323 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Imai,Y.,Ishikawa,T.et al.: "Mutational analysis of the p53 and K-ras genes and allelotype study of the Rb-1 gene for investigating the pathogenesis of combined hepatocellular -cholangio-cellular carcinomas." Jpn.J.Cancer Res.87. 1056-1062 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Arai,M.,Ishikawa,T.et al.: "Genetic alterations in adenocarcinomas of the small intestine." Recent Advances in Gastroenterological Carcinogenesis I. 333-336 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Oda,H.,Ishikawa,T.et al.: "Loss of p53 is an early event in induction of brain tumors in mice by transplacental carcinogen exposure." Cancer Res.57. 646-650 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Arai,M.,Ishikawa,T.et al.: "Mutations of the Ki-ras,p53 and APC genes in adenocarcinomas of the human small intestine." Int.J.Cancer. 70. 390-395 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Aoki, K., Nakatsuru, Y., Sakurai, J., Sato, A., Prince Masahito and Ishikawa, T.: "Age-dependence of O^6-methylguanin-DNA methyltransferase activity and its depletion after carcinogen treatment in the teloeost, medaka (Oryzias latipes)." Mutation Res.293. 225-231 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsumoto, J., Akiyama, T., Nemoto, N., Prince Masahito and Ishikawa, T.: "Appearance of tumorous phenotypes in goldfish erythrophores transfected with the oncogene (ras, src, and myc) and their spontaneous redifferentiation in vitro." J.Invest. Dermatol.100 suppl.214S-221S (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakatsuru, Y., Matsukuma, S., Nemoto, N., Sugano, H., Sekiguchi, M.and Ishikawa, T.: "O^6-methylguanine-DNA methyltransferase protects against nitrosamin-induced hepatocarcinogenesis." Proc. Natl. Acad. Sci. USA. 90. 6468-6472 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Zarkovic M., Qin, X., Nakatsuru, Y., Oda, H., Nakamura, T., Shamsuddin, A.M.and Ishikawa, T.: "Tumor promotion by fecapentaene-12 in a rat colon carcinogenesis model." Carginogenesis. 14. 1261-1264 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuwashima, Y., Nemoto, N.and Ishikawa, T.: "Expression of proto-oncogenes and cytoskeltal actin gene in foreign body-induced murine sarcomas." Invivo. 7. 139-142 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakamura, T., Nemoto, T., Arai, M., Yamazaki, Y., Kasuga, T., Gutmann, D.H., Collins F.S.and Ishikawa, T.: "Specific expression of the neurofibromatosis type 1 gene (NF1) in the hamster schwann cell." Amer. J.Path. 144. 549-555 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakamura, T., Ushijima, T., Ishizuka, Y., Nagao, M., Arai, M., Yamazaki, Y.and Ishikawa, T.: "Cloning and activation of the Syrian hamster neu proto-oncogene." Gene. 140. 251-255 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakamura, T., Ushijima, T., Ishizaka, Y.Nagao, M., Nemoto, T., Hara, M.and Ishikawa, T.: "neu proto-oncogene mutation is specific for the neurofibromas in a N-nitroso-N-ethylurea-induced hamster neurofibromatosis model but not for hamster melanomas and human schwann cell tumors." Cancer Res.54. 976-980 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakamura, T., Ishizaka, Y., Nagao, M., Hara, M.and Ishikawa, T.: "Expression of the ret proto-oncogene product in human normal and neoplastic tissues of neural crest origin." J.Pathol.172. 255-260 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kurihara, Y., Kurihara, H., Suzuki, H., Kodama, T., Maemura, K., Nagai, R., Oda, H., Kuwaki, T., Cao, W.H., Kamada, N., Jishage, K., Ouchi, Y., Azuma, S., Toyoda, Y., Ishikawa, T., Kumada, M.and Yazaki, Y.: "Elevated bood pressure and craniofacial abnormlities in mice dificient in endothelin-1." Nature. 368. 703-710 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Qin, X., Zarkovic, M., Nakatsuru, Y., Arai, M., Oda, H.and Ishikawa, T.: "DNA adduct formation and assessment of aberrant crypt foci in vivo in the rat colon mucosa after treatment with N-methyl-N-nitrosourea." Carcinogenesis. 15. 851-855 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakatsuru, Y., Tsuchiya, E., Nakagawa, K., Nemoto, N., Oda, H.and Ishikawa, T.: "O^6-methylguanine-DNA methyltransferase activity in the human lung persists with advancing age." Gerontology. 40. 3-9 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Qin, X., Zhang, S., Nakatsuru, Y., Oda, H., Yamazaki, Y., Suzuki, T., Nikaido, O.and Ishikawa, T.: "Active repair of UV-photoproducts in monokey skin in vivo by quantitative immunohistochemistry." Cancer Lett.83. 291-298 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Oda, H., nakatsuru, Y.and Ishikawa, T.: "Mutation of the p53 gene and p53 protein overxpression are associated with sarcomatoid transformation in renal cell carcinoma." Cancer Res.55. 658-662 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Oda, H., Nakatsuru, Y., Imai, Y., Sugimura, H.and Ishikawa, T.: "A mutational hot spot in the p53 gene is associated with hepatoblastoma." Int. J.Cancer. 60. 786-790 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakane, H., Takeuchi, S., Yuba, S., Saijo, M., Nakatsu, Y., Murai, H., Nakatsuru, Y., Ishikawa, T., Hirota, S., Kitamura, Y., Kato, Y., Tsunoda, Y., Miyauchi, H., Horio, T., Tokunaga, T., Matsunaga, T., Nikaido, O., Nishimune, Y., Okada, Y.and Tanaka, K.: "High incidence of UVB or chemical carcinogen-induced skin tumorigenesis in mice lacking the xeroderma pigmentosum grouop A (XPA) gene." Nature. 377. 165-168 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Qin, X., Zhang, S., Zarkovic, M., Yamazaki, Y., Oda, H., Nakatsuru, Y., Ishikawa, T.and Ishikawa, T.: "Inhibitory effect of probucol on nephro-toxicity induced by ferric nitrilotriacetate (Fe-NTA) in rats." Carcinogenesis. 16. 2549-2552 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Zarkovic, M., Qin, X., Nakatsuru, Y., Zhang, S., Yamazaki, Y., Oda, H., Ishikawa, T.and Ishikawa, T.: "Inhibitory effect of probucol on benzo [a] pyrene-induced lung tumorigenesis." Carcionogenesis. 16. 2599-2601 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Imai, Y., Oda, H., Nakatsuru, Y.and Ishikawa, T.: "A polymorphism at codon 160 of human O^6-methylguanine-DNA methyltransferase gene in young patients with adult type cancers and functional assay." Carcinogenesis. 16. 2441-2445

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Qin, X., Zhang, S., Oda, H., Nakatsuru, Y., Shimizu, S., Yamazaki, Y., Nikaido, O., Ishikawa, T.: "Quantitative detection of ultraviolet light-induced photoproducts in mouse skin by immunohistochemistry." Jpn. J.Cancer Res.86. 1041-1048 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kurihara, Y., Kurihara, H., Oda, H., Maemura, K., Nagai, R., Ishikawa, T.and Yazaki , Y.: "Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1." J.Clin. Invest.96. 293-300 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsuzuki, T., Sakumi, K., Shiraishi, A., Kawate, H., Igarashi, H., Iwakuma, T., Tominaga, Y., Zhang, S., Shimizu, S., Ishikawa, T., Nakamura, K., Nakao, K., Katsuki, M.and Sekiguchi, M.: "Hypesensitivity to alkylating agent of mice deficinet in the methyltransferase gene." Carcinogenesis. 17. 1215-1220 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Qin, X., Zhang, S., Zarkovic, M., Nakatsuru, Y., Shimizu, S., Yamazaki, Y., Oda, H., Nikaido and Ishikawa, T.: "Detection of ultraviolet-photoproducts in mouse skin exposed natural sunlight." Jpn. J.Cancer Res.87. 685-690 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Oda, H., Imai, Y., Nakatsuru, Y., Hata, J and Ishikawa, T.: "Somatic mutations of the APC gene in sporadic hepatoblastomas." Cancer Res.56. 3320-3323 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Imai, Y., Oda, H., Arai, M., Shimizu, S., Nakatsuru, Y., Inoue, T.and Ishikawa, T.: "Mutational analysis of the p53 and K-ras genes and allelotype study of the Rb-1 gene for investigating the pathogenesis of combined hepatocellular-cholangio-cellular carcinomas." Jpn. J.Cancer Res.87. 1056-1062 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Arai, M., Shimizu, S., Imai, Y., Nakatsuru, Y., Oda, H., Murakami, T., Endo, H., Oohara, T.and Ishikawa, T.: "Genetic alterations in adenocarcinomas of the small intestine." Recent Advances in Gastroenterological Carcinogenesis I. 333-336 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Oda, H., Zhang, S., Tsurutani, N., Shimizu, S., Nakatsutu, Y., Aizawa, S.and Ishikawa, T.: "Loss of p53 is an early event in induction of brain tumors in mice by transplacental carcinogen exposure." Cancer Res.57. 646-650 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Arai, M., Shimizu, S., Imai Y., Nakatsuru, Y., Oda, H., Oohara, T.and Ishikawa, T.: "Mutations of the Ki-ras, p53 and APC genes in adenocarcinomas of the human smass intestine." Int. J.Cancer. 70. 390-395 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Suwiwat, S., Oda, H., Shimizu, Y.and Ishikawa, T.: "Prevalence of p53 muatations and protein expression in esophageal cancers in southern Thailand Int." J.Cancer Res.(in press). (1997)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-03-09  

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