| Co-Investigator(Kenkyū-buntansha) |
KURA Shinobu Graduate school of Medical Sciences, Kyushu University, Assistant Professor, 大学院・医学系研究科, 助手 (90037391)
HAYAKAWA Hiroshi Graduate school of Medical Sciences, Kyushu University, Assistant Professor, 大学院・医学系研究科, 助手 (70150422)
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| Budget Amount *help |
¥5,300,000 (Direct Cost: ¥5,300,000)
Fiscal Year 1998: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Research Abstract |
Oxidative DNA damage is thought to contribute to carcinogenesis, aging, and neurological degeneration. Studies have shown that oxidative DNA damage accumulates in cancerous tissue. For example, higher levels of oxidative base damage were observed in lung cancer tissue compared with surrounding normal tissue. Another study reported a 9-fold increase in 8-oxoG, 8-hydroxyadenine, and 2,6-diamino-4-hydroxy-5-formamidopyrimidine in DNA from breast cancer tissue compared with normal tissue. Further, the cumulative risk of cancer increases dramatically with age in humans. In genreal terms cancer can be regarded as a degenerative disease of ageing. There is evidence for the accumulation of oxidative DNA damage with age based on studies mainly measuring an increase in 8-oxoG.
8-Oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) is formed in the nucleotide pool of a cell during normal cellular metabolism. When incorporated into DNA, 8-oxo-dGTP causes mutation. Organisms posseces 8-oxo
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-dGTPase, an enzyme that specifically degrades 8-oxo-dGTP to 8-oxo-dGMP. By means of gene targeting, we established mouse lines deficient in the MTH1 gene, and 8-oxo-dGTPase activity. An approximately 2-fold higher frequency of spontaneous mutations in the HPRT gene was observed in two independently isolated MTH1-/- ES cell lines, compared with the value of MTH1+/+ cells. We then examined susceptibility of the derived mutant mice to spontaneous tumorigenesis. Wild type or mutant mice consisting of approximately 50 male and 50 female were maintained under SPF conditions and necropsied after 1.5 years. No significant difference in survival rates of MTH1+/+ and MTH1-/- mice. However, pathological examination revealed a statistically significant difference in the incidence of tumors. A distinct difference in the frequency of tumor formation in lungs between wild-type and mutant mice was observed while more tumors were likely to be formed in the stomach and in liver of MTH1-/- mice as well. 8-Oxo-dGTPase appears to play an important role to protect animals from the spontaneous tumorigenesis caused by the oxygen-induced DNA damage.
The MTH1-deficient mouse provides a new and useful model system in which to explore the in vivo role of the MTH1 protein in normal and under oxidative stress. Less
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