DIFFERENCES IN RADIATION-INDUCED MICRONUCLEI YIELDS OF HUMAN-CELLS - INFLUENCE OF RAS GENE-EXPRESSION AND PROTEIN LOCALIZATION

Expression of ras has been correlated with increased intrinsic resista nce to ionizing radiation. In this study we show that increased EJras expression in human cells is associated with a decrease in the frequen cy of radiation-induced micronuclei. The experimental system consisted of human osteosarcoma-derived cell lines which quantitatively vary in their EJras expression. There was a dose-dependent relationship betwe en radiation dose and micronuclei formation in all cell lines tested. Human osteosarcoma cells, in which the ras level was undetectable, had the highest frequency of micro-nuclei production at all radiation dos es tested. At 4 Gy the most radioresistant cells exhibited a 41.5 +/- 5% decrease in the production of micronuclei concomitant with high ras expression in comparison with the relatively radiosensitive parental cell line. Cells expressing a low amount of EJras demonstrated a 23 +/ - 3% decrease in micronuclei induction compared with parental cells. T reatment of cells with lovastatin, an inhibitor of ras-encoded p21ras post-translational processing via the mevalonate pathway, markedly dec reased the yield of micronuclei formation in cells transfected with ra s; the drug had no effect on radiation-induced micronuclei formation i n parental cells. The use of the in vitro micronuclei assay has provid ed a convenient way to visualize differences in the genotoxic damage i nduced by ionizing radiation in cells which express different amount o f Ejras. The results indicate that elevation of ras expression in huma n cells can lead to a decrease in the number of radiation-induced micr onuclei formed and that this relationship is dependent on membrane ass ociation of ras-encoded p21.