Journal
ONCOGENE
Volume 20, Issue 17, Pages 2144-2152Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1204309
Keywords
K-ras; DNA damage; ES cells; apoptosis
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The roles of K-ras in neoplasia are not entirely understood, although there is evidence that K-ras affects susceptibility to apoptosis, modulating survival of DNA damaged cells which would otherwise be eliminated. In this study, we investigated the effects of mutant K-ras on apoptosis in vitro following DNA damage. To avoid complications resulting from mutations in other cancer-related genes and from the presence of endogenous K-ras, we derived K-ras null embryonic stem cells. Expression of either wild-type or mutant K-vas was reconstructed by stable plasmid transfection, The cell lines were treated with etoposide, cisplatin and UV radiation and apoptosis measured flow cytometrically. Mutant K-ras potentiated the effect of etoposide-derived DNA damage by increasing apoptosis, whereas absence of K-ras had the opposite effect. This pattern was similar but less marked with cisplatin, whereas UV yielded no difference in apoptosis with regard to K-ras status, suggesting that the effect of K-ras on apoptosis is dependent on the nature of the DNA damage, To investigate possible mechanisms, we examined the expression of p19(ARF) mRNA by RT-PCR, Cells expressing mutant K-ras produced elevated levels of p19(ARF) mRNA, which could link K-ras status with p53 expression and hence susceptibility to DNA damage-induced apoptosis.
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