| Project/Area Number |
09358015
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Molecular biology
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| Research Institution | Fukuoka Dental College |
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Principal Investigator |
SEKIGUCHI Mutsuo Fukuoka Dental College, Dept. of Biology, Professor, 歯学部, 教授 (00037342)
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| Co-Investigator(Kenkyū-buntansha) |
ITO Riyoko Fukuoka Dental College, Dept. of Biology, Research Associate, 歯学部, 助手 (10140865)
SHIMOKAWA Hidetoshi Fukuoka Dental College, Dept. of Biology, Research Associate, 歯学部, 助手 (50122792)
SANADA Masayuki Fukuoka Dental College, Lecturer, 歯学部, 講師 (40084264)
TSUZUKI Teruhisa Kyushu Universtiy. Faculty of Medicine, Professor, 医学部, 教授 (40155429)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥24,200,000 (Direct Cost: ¥24,200,000)
Fiscal Year 1999: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1998: ¥8,200,000 (Direct Cost: ¥8,200,000)
Fiscal Year 1997: ¥11,000,000 (Direct Cost: ¥11,000,000)
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| Keywords | Carcinogen / DNA repair enzyme / mismatch repair / gene-defective mice / alkylating agents / cell death / cancer / mutation / DNA修復系 / 発がん物質 / 検出・評価システム / DNA修復 / アポトーシス / 酸素マジカル / 発がん / 修復欠損 / 遺伝子ターゲティング / 致死効果 |
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| Research Abstract |
Mice with mutation in both alleles of the Mgmt and the Mlh1 gene, the former encoding a DNA repair methyltransferase and the latter a protein functioning at an early step of mismatch repair, are as resistant to the killing action of alkylating agents as are wild-type mice. These mice yielded a large number of tumors, when exposed to alkylating carcinogens, but this characteristic was subdued since they also showed a relatively high level of spontaneous tumorigenistiy, as the consequence of the defect in mismatch repair. This complexity is now resolved by introducing the Mlh1+/- mutation, instead of Mlh1-/-, in these methyltransferase-deficient mice. MlmtィイD1-/-ィエD1 Mlh1ィイD1+/-ィエD1 mice with about half the amount of MLH1 protein as MgmtィイD1-/-ィエD1 Mlh1ィイD1+/+ィエD1 mice, were resistant to the killing action of N-methyl-N-nitrosourea (MNU), up to the level of 30 mg/kg of body weight. Eight weeks after exposure to this dose of MNU, 40% of MNU-treated MgmtィイD1-/-ィエD1 Mlh1ィイD1+/-ィエD1 mice had thymic lymphoma and there was no tumor in these mice not given the treatment. It seems that the cellular content of MLH1 protein is a critical factor for determining if damaged cells enter into either one of the two pathways, leading to mutation induction and to apototic cell death. Loss of Mlh1 expression was frequently observed with tumors of MgmtィイD1-/-ィエD1 Mlh1ィイD1+/-ィエD1 mice, and this might be related to progression of the tumors.
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