ucn-1028-c and 6-hydroxy-2-5-7-8-tetramethylchroman-2-carboxylic-acid

We have examined the effects of three structurally distinct antioxidants (N-acetylcysteine [NAC], Trolox C [a water-soluble vitamin E derivative], and nordihydroguaiaretic acid [NGA]) on the expression of the c-fos gene over a 2-hour period. Determination of cellular glutathione concentration (the primary determinant of the cellular redox state) over the same time-course verifies that all the compounds studied cause an increase in cellular reduction potential. The level of c-fos messenger RNA increased rapidly in response to micromolar concentrations of these compounds, reaching a peak in 30-60 minutes. Induction of c-fos expression by these antioxidants is at least partly due to an increase in transcription, as determined by nuclear run-on assay. Down regulation of protein kinase C (PKC) by pretreatment for 24 hours with 500 nm PMA prevents induction by subsequent stimulation with either PMA or NGA. NAC induction of c-fos is unaffected by PMA pretreatment, while Trolox C superinduced c-fos following PMA pretreatment. None of these treatments stimulated translocation of PKC-alpha from the cytosol to the membrane. These results suggest that increasing the intracellular reducing potential induces c-fos expression through multiple pathways.

Topics: Acetylcysteine; Antioxidants; Blotting, Northern; Carcinogens; Chromans; Enzyme Inhibitors; Fetus; Fibroblasts; Free Radical Scavengers; Gene Expression Regulation; Glutathione; Humans; Lung; Masoprocol; Naphthalenes; Protein Kinase C; Proto-Oncogene Proteins c-fos; RNA, Messenger; Signal Transduction; Tetradecanoylphorbol Acetate; Transcriptional Activation