Influence of the glucocorticoid receptor on c-fos inducibility in activated ras-containing mouse lung cells

✍ Scribed by Todd A. Johnson; Jia Li; David G. Beer

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 951 KB
• Volume: 17
• Category: Article
• ISSN: 0899-1987
• DOI: 10.1002/(sici)1098-2744(199610)17:2<70::aid-mc3>3.0.co;2-x

✦ Synopsis

Glucocorticoids inhibit the growth and promote the differentiation of normal lung cells. Transformed A5 mouse lung cells containing an activated Ki-ras gene are not responsive to glucocorticoid-induced growth inhibition and demonstrate increased cell proliferation. Activated ras genes may lead to constitutive activation of genes, such as the activating protein 1 (AP-1) transcription factor components fos andjun, which are downstream in the ras signal-transduction pathway. A5 cells and A5GR, a stable A5 transfectant containing excess copies of the glucocorticoid receptor (GR) gene, were examined for potential alterations in AP-1 that accompany t h e restoration of glucocorticoid-dependent growth inhibition. The established ability of the GR to antagonize AP-1 activity led us to examine the regulation and inducibility of c-fos and c-jun in these cells. Nontransformed C10 lung cells were found to have higher and more inducible AP-1 activity than the transformed A5 cells. The level of AP-1 activity could be reduced in C10 cells by transient transfection of constitutive fos and jun expression vectors. In A5 cells, stimulation with factors that activate the serum-response element on the fos promoter and induce c-fos mRNA had little effect on AP-1 activity, whereas treatment with 12-0tetradecanoylphorbol-13-acetate, which acts at the fos-AP-1 binding sequence site on the fos promoter, eff iciently induced c-fos mRNA. The c-fos mRNA in A5GR cells, however, was not inducible with all treatments, suggesting that one potential mechanism by which the GR restores glucocorticoid-induced growth inhibition in these cells may involve the desensitization of additional 12-0-tetradecanoy1phorbol-13-acetate-inducible elements of the fos promoter.