| Research Abstract |
Among the oxidized molecules caused by reactive oxygen spices, 8-oxoguanine (8-oxoG) is mutation prone molecule as it pairs with adenine as well as cytosine during DNA replications, resulting in transversion mutations. 8-Oxoguanine-DNAglycosylase, encoded by the ogg1 gene, removes the oxidized base from DNA. Another enzyme, 8-oxo-dGTPase that is the mthl gene product, degrades an oxidized DNA precursor, 8-oxo-dGTP into 8-oxo-dGMP and pyrophosphate. To evaluate the role of each enzyme in prevention of tumorigenesis, we produced the knockout mice for oggl and mth1 genes.
Lung adenoma/carcinoma was spontaneously developed in the ogg1 knockout mice about 1.5 year after birth. The lung tumor associated with ogg1 knockout genotype was suppressed by an additional mutation of the mth1 gene which encodes another 8-oxoguanine excluding enzyme, 8-oxo-dGTPase. To obtain the mice with four kinds of genotypes, the mth1+/+, ogg1+/+, the mth1-/-, ogg1+/+, the mth1+/+, ogg1-/-, and the mth1-/-, ogg1-/-,
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the mth1+/-, ogg1+/+ male was crossed with the mth1+/+, ogg1+/- female to produce mth1+/-, ogg1+/- mice. From the progenies resulted by inbreeding the mice, we selected the mice with four kinds of genotype for a spontaneous tumorigenesis experiment. The mice were grown under the special pathogen free condition, and examined at 580(±1) days after birth, for spontaneously developed tumors. Six out of 14 mth1+/+, ogg1-/- mice carried lung adenoma/carcinoma, and some of the mice have numbers of tumors in the different lobi. The mean number of tumors per mouse is 0.71, which is 5 times more than that of the wild type mouse (0.14). We obtained a similar result from a different experiment using the ogg1+/+ and the ogg1-/- mice examined between 69 and 75 weeks after birth. The latter experiment also showed that there is little difference in numbers of liver and intestinal tumors between the groups. Since there are reports that mutations exist in ogg1 gene in the human lung cancer, the ogg1 should act as a lung tumor suppressor gene in mammalians. Less
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