Identification of effetor molecules for reactive oxygen species and its biological significance

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Recent studies have clarified that reactive oxygen species(ROS)are involved in a diversity of biological phenomena including radiation damage, carcinogenesis, ischemia-reperfusion injury, diabetes mellitus and neurodegenerative diseases. In this project we have established methods to localize ROS-induced damage in paraffin-embedded specimens. This owes to a successful production of antibodies against covalently modified structures specific for ROS-induced damage. The epitopes include 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins. This technique was applied to animal models of human specimens of diabetes mellitus, reperfusion injury, arsenic intoxication, colon cancer, viral hepatitis as well as oxidative stress-induced cancer model of rats using ferric nitrilotriacetate(Fe-NTA). Then, we have answered a question whether there are target genes in the oxidative stress-induced carcinogenesis by genetic analysis using F1 hybrid rats. This study revealed that chromosome 5 and 8 of rats showed a high incidence of loss of heterozygosity with PCR microsatellite analyses, which finally lead to a conclusion that p15/p16 tumor suppressor gene is one of the major target genes in this oxidative stress-induced carcinogenesis model.