Biological phenomena caused by 8-oxoguanine in DNA

• Project/Area Number: 12680814
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: KYUSHU UNIVERSITY
• Principal Investigator: SAKUMI Kunihiko Med. Inst. Bioreg., KYUSHU UNIVERSITY, Ass. Prof., 生体防御医学研究所, 助手 (50211933)
• Project Period (FY): 2000 – 2001
• Project Status: Completed (Fiscal Year 2001)
• Budget Amount: ¥4,000,000 (Direct Cost: ¥4,000,000); Fiscal Year 2001: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2000: ¥2,600,000 (Direct Cost: ¥2,600,000)
• Keywords: gene-disrupted mouse / ogg1 gene / 8-oxoguanine / mutation / lung tumor / mth1 gene

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-/-, 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.

Research Products

• [Publications] Tsuchimoto, D. et al.: "Human APE2 protein is mostly localized in the nuclei and to some extent in the mitochondria, while nuclear APE2 is partly associated with proliferating cell nuclear antigen"Nucleic Acids Res.. 29. 2349-2360 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Nakabeppu, Y. et al.: "Mechanisms protecting genomic integrity from damage caused by reactive oxygen species : Implications for carcinogenesis and neurodegeneration"Environ. Mutagen Res.. 23. 182-195 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Nishioka, T. et al.: "fosB gene products trigger cell proliferation and morphologicalalteration with an increased expression of a novel processed form of galectin-1 in the rat 3Y1 embryo cell line"J. Biochem. (in press).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Tsuchimoto, D. et al.: "Human APE2 protein is mostly localized in the nuclei and to some extent in the mitochondria, while nuclear APE2 is partly associated with proliferating cell nuclear antigen"Nucleic Acids Res.. Vol. 29. 2349-2360 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Nakabeppu,Y. et al.: "Mechanisms protecting genomic integrity from damage caused by reactive oxygen species: Implications for carcinogenesis and neurodegeneration"Environ. Mutagen Res.. Vol. 23. 182-195 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Nishioka, T. et al.: "fosB gene products trigger cell proliferation and morphologicalalteration with an increased expression or a novel processed form of galectin-1 in the rat 3Y1 embryo cell line"J. Biochem.. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Tsuchimoto, D. et al.: "Human APE2 protein is mostly localized in the nuclei and so some extent in the mitochondria, while nuclear APE2 is partly associated with proliferating cell nuclear antigen"Nucleic Acids Res.. 29. 2349-2360 (2001)
• [Publications] Nakabeppu, Y. et al.: "Mechanisms protecting genomic integrity from damage caused by reactive oxygen species : Implications for carcinogenesis and neurodegeneration"Environ. Mutagen Res.. 23. 182-195 (2001)
• [Publications] Nishioka, T. et al.: "fosB gene products trigger cell proliferation and morphologicalalteration with an increased expression of a novel processed form of galectin-1 in the rat 3 y 1 embryo cell line"J. Biochem.. (in press).
• [Publications] Shiraishi,A. et al.: "Increased susceptibility to chemotherapeutic alkylating agents of mice deficient in DNA repair methyltransferase."Carcinogenesis. 21. 1879-1883 (2000)
• [Publications] Kawate,H. et al.: "A defect in a single allele of the Mlh1 gene causes dissociation of the killing and tumorigenic actions of an alkylating carcinogen in methyltransferase-deficient mice"Carcinogenesis. 21. 301-305 (2000)