THE NEPHROTOXIN DICHLOROVINYLCYSTEINE INDUCES EXPRESSION OF THE PROTOONCOGENES C-FOS AND C-MYC IN LLC-PK(1) CELLS - A COMPARATIVE INVESTIGATION WITH GROWTH-FACTORS AND 12-O-TETRADECANOYLPHORBOLACETATE

Previous studies in kidney cells showed that S-(1,2-dichlorovinyl)-L-cysteine (DCVC) induces both direct DNA damage and DNA double-strand breaks by activation of Ca2+-dependent endonucleases. The objective of this study was to investigate the effects of DCVC on the expression of the protooncogenes c-fos and c-myc in cultured kidney cells (LLC-PK1). Supplementation of the incubation medium with 10% FCS after 24 hr incubation in 0.2% FCS resulted in a clear, but comparatively weak induction of the expression of c-fos and c-myc in LLC-PK1 cells. Addition of 500 mum DCVC to the high serum incubation medium induced a further three-fold increase of the transcript levels. A similar increase in the absolute amount of c-fos mRNA was induced by a mixture of growth factors (epidermal growth factor/insulin/transferrin) and of c-myc mRNA with 12-O-tetradecanoylphorbolacetate. However, the kinetics of gene expression were different. In the presence of DCVC the expression of c-fos and c-myc increased continuously in a time-dependent manner during the entire incubation period. In contrast, with growth factors and 12-O-tetradecanoyl-phorbolacelate the maximum transcript levels were detected after 0.5 hr (c-fos) and 1 hr (c-myc), respectively; thereafter, a slight decrease was observed up to the end of the incubation time.