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Influence of the glucocorticoid receptor on c‐fos inducibility in activated ras ‐containing mouse lung cells
Author(s) -
Johnson Todd A.,
Li Jia,
Beer David G.
Publication year - 1996
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/(sici)1098-2744(199610)17:2<70::aid-mc3>3.0.co;2-x
Subject(s) - biology , glucocorticoid receptor , glucocorticoid , transfection , microbiology and biotechnology , c fos , signal transduction , transcription factor , immediate early gene , cell culture , gene expression , receptor , gene , endocrinology , biochemistry , genetics
Abstract 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. © 1996 Wiley‐Liss, Inc.