The c-fos serum response element (SRE) confers negative response to glucocorticoids.
Ligand activated Glucocorticoid Receptor (GR), specifically inhibited the serum induced c-fos promoter activation in NIH3T3 fibroblasts. The negative control was mediated by the c-fos SRE and correlated with the relative abundance of active GR. Serum activated SRE was repressed 3-4-fold by glucocorticoids irrespective of the promoter context (heterologous or authentic). The suppressing ability of GR was absolutely dependent on its DNA binding domain (DBD), since deletion of this region left the serum induction unimpaired. The methylation interference pattern of GR revealed two distinct binding sites within the SRE and identified the GR contact bases, important also for binding and function of SRE targeted transcription factors, such as the Serum Response Factor (SRF) and the p62 Ternary Complex Factor (TCF). We conclude that GR binds to c-fos SRE and inhibits c-fos promoter activation by antagonizing the function of positive transcription factors targeting to overlapping or identical sites. Since the c-fos SRE is activated by multiple mitogenic signalling pathways, inactivation by GR could explain, at least in part, the growth inhibitory response of fibroblasts to glucocorticoid hormones.
Karagianni
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National Hellenic Research Foundation, Institute of Biological Research and Biotechnology, Athens, Greece.
Tsawdaroglou
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N
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000502:physiology; D026362:Serum Response Factor; D014157:Transcription Factors / Q000037:antagonists & inhibitors*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011965:Receptors, Glucocorticoid; D026362:Serum Response Factor; D014157:Transcription Factors; D003907:Dexamethasone