Influence of the glucocorticoid receptor on c-fos inducibility in activated ras-containing mouse lung cells.
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 and jun, 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 the 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-O-tetradecanoylphorbol-13-acetate, which acts at the fos-AP-1 binding sequence site on the fos promoter, efficiently 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-O-tetradecanoylphorbol-13-acetate-inducible elements of the fos promoter.
Department of Surgery, University of Michigan, Ann Arbor 48109, USA.
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Johnson
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D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D016762:Genes, fos; D016758:Genes, jun; D011905:Genes, ras; D008168:Lung / Q000166:cytology; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism
D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1