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Oxidative stress-induced intestinal tumorigenesis in mice with a targeted disruption
Teruhisa Tsuzuki, D. Sc.
Department of Medical Biophysics and Radiation Biology
Oxygen radicals are produced through normal cellular metabolism, and the formation of such radicals is further enhanced by ionizing radiation and by various chemicals. The oxygen radicals attack DNA and its precursor nucleotides, and consequently induce various oxidized forms of bases in DNA within normally growing cells. Among such modified bases, 8-oxo-7, 8-dihydroguanine (8-oxoG) and 2-hydroxyadenine (2-OH-A) are highly mutagenic lesions, if not repaired. MUTYH, a mammalian ortholog of E. coli MutY, is a DNA glycosylase that excises adenine and 2-OH-A incorporated opposite 8-oxoG or guanine, thus considered to prevent G:C to T:A transversions in mammalian cells. Recently, biallelic germ-line mutations of MUTYH gene have been found in patients predisposed to a recessive form of hereditary multiple colorectal adenoma and carcinoma. Tumor analyses from the patients revealed a significant excess of G:C to T:A somatic mutations in the APC gene. To investigate the role of the MUTYH gene in mutagenesis and tumorigenesis, we have established Mutyh gene-knockout mice by gene targeting. The Mutyh-deficient mice appeared normal in their development and growth but showed a marked predisposition to spontaneous tumorigenesis in various tissues when examined at 18 months of age. The incidence of adenoma/carcinoma in the intestine was significantly increased in Mutyh-deficient mice, as compared with wild-type mice. This high susceptibility of Mutyh-deficient mice to intestinal tumor-development was well correlated with the observation in MAP (MUTYH associated polyposis) patients.

(Collaborative project with Prof. Y. Nakabeppu’s group, Medical Institute of Bioregulation, Kyushu University)

Figure: KBrO3-induced tumors in the small intestine of MUYTH-null mice.

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