1995 Fiscal Year Final Research Report Summary
Importance of DNA repair in carcinogenesis : Insight for transgene or gene targeting experiments.
| Project/Area Number |
06454191
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Experimental pathology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
NAKATSURU Yoko ASISTANT,THE SECOND DEPARTMENT OF PATHOLOGY,FACULTY OF MEDICINE UNIVERSITY OF TOKYO, 医学部(医), 助手 (00237314)
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| Co-Investigator(Kenkyū-buntansha) |
ODA Hideaki ASSOCIATE PROFESSOR,THE SECOND DEPARTMENT OF PATHOLOGY,FACULTY OF MEDICINE,UNIVE, 医学部(医), 助教授 (40214142)
ISHIKAWA Takatoshi PROFESSOR,THE SECOND DEPARTMENT OF PATHOLOGY,FACULTY OF MEDICINE,UNIVERSITY OF T, 医学部(医), 教授 (30085633)
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| Project Period (FY) |
1994 – 1995
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| Keywords | DNA repair / O^6 -methylguanine / Methyltransferase / Transgenic mouse / Gene targeting mouse / Xeroderma pigmentosum / Animal model for disease |
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| Research Abstract |
In our research project, we studied about relationship between DNA repair system and carcinogenesis using transgenic animals.
1) We generated the transgenic mice (ada mouse) introduced with bacterial DNA repair enzyme gene, O^6-methylguanine-DNA methyltransferase (MGMT ; ada) gene The ada gene was highly expressed in the liver and the enzyme activity in the liver was 3 times higher in transgenic mouse than in the nontransgenic mouse.Using ada mice and nontransgenic control mice, we already reported that 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 generaly known to develop spontaneous liver tumors at high incidence in later life. In this project, we compared the incidences of spontaneous liver tumors between ada mice and nontransgenic mice. In results, both groups developed liver tumours at the same incidence (48%). However, the
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histological examination showed the incidence of hepatocellular carcinoma in ada mouse was significantly lower than in nontransgenic mouse. These obserbations suggest that MGMT may also protect mice from tumor progression.
2) It is well known that Xeroderma pigmentosum (XP) patients are deficient in DNA repair. The availability of XPA (XP group A complementing) gene knockout mice generated by Dr.Tanaka's group at Osaka University has enabled us to investigate that functional role of XPA nucleotide excision repair in gene initiation and promotion of carcinogenesis in vivo, using the mouse skin as a model system. XPA null mice demonstrated skin ulcers 5 to 7 days after DMBA treatment. Subsequent experiment in which XPA null mice were repeatedly trated with DMBA at weekly intervals revealed that papillomas first arrise in XPA null mice between 10 and 16 weeks in which a 100% incidence was achieved. Heterozygous and wild-type mice showed an almost zero or very much lower yield of papillomas. Results obtained from the above two separate animal models provide direct evidence that DNA repair protects mice from DNA damage elicited by chemical carcinogens.
3) It is well known that the p53 gene deficient mice develop spontaneous tumors in early life. The most frequent tumor type in homozygotes was malignant lymphoma ; in heterozytotes, osteosarcomas and soft tissue sarcomas predominated. In our project, the p53 deficient mice (generated by Aizawa et al., Kumamoto Univ.) were treated with ethylnitrosourea transplacentaly at 12-16 pregnant day. Seventy percent of homozygous and 4% of heterozyous mice developed brain tumors by the age of 3 to 4 months. None were observed in wild mice. Less
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[Publications] Qin, X., Zhang, S., Nakatsuru, Y., Oda, H., Yamazaki, Y., Suzuki, T., Nikaido, O.and Ishikawa, T.: "Detection of active UV-photoproduct repair in monkey skin in vivo by quantitative immunohistochemistry" Cancer lett. 83. 291-298 (1994)
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「研究成果報告書概要(欧文)」より
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[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)
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「研究成果報告書概要(欧文)」より
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[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 ultraviolet-B or chemical-carcinogen-induced skin tumours in mice lacking the xeroderma pigmentosum group A gene" Nature. 377. 165-168 (1995)
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「研究成果報告書概要(欧文)」より
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[Publications] Qin, X., Zhang, S., Oda, H.Nakatsuru, Y., Shimizu, S., Yamazaki, Y., Nikaido, O.and Ishikawa, T.: "Quantitative detection of ultraviolet light-induced photoproducts in mouse skin by immunohistochemistry" Jpn.J.Cancer Res.86. 1041-1048 (1995)
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[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." Carcinogenesis. 16. 2599-2601 (1995)
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「研究成果報告書概要(欧文)」より
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[Publications] Qin, X., Zhang, S., Zarkovic M., Yamazaki, Y., Oda, H., Nakatsuru, Y., Ishikawa, T.and Ishikawa, T: "Inhibitory effect of probucol on nephrotoxicity induced by ferric nitrilotriacetate(Fe-NTA)in rats." Carcinogenesis. 16. 2549-2552 (1995)
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