Opposing effects of corepressor and coactivators in determining the dose-response curve of agonists, and residual agonist activity of antagonists, for glucocorticoid receptor-regulated gene expression.
A distinguishing, but unexplained, characteristic of steroid hormone action is the dose-response curve for the regulation of gene expression. We have previously reported that the dose-response curve for glucocorticoid induction of a transfected reporter gene in CV-1 and HeLa cells is repositioned in the presence of increasing concentrations of glucocorticoid receptors (GRs). This behavior is now shown to be independent of the reporter, promoter, or enhancer, consistent with our proposal that a transacting factor(s) was being titrated by added receptors. Candidate factors have been identified by the observation that changes in glucocorticoid induction parameters in CV-1 cells could be reproduced by varying the cellular levels of coactivators [transcriptional intermediary factor 2 (TIF2), steroid receptor coactivator 1 (SRC-1), and amplified in breast cancer 1 (AIB1)], comodulator [CREB-binding protein (CBP)], or corepressor [silencing mediator for retinoid and thyroid-hormone receptors (SMRT)] without concomitant increases in GR. Significantly, the effects of TIF2 and SMRT were mutually antagonistic. Similarly, additional SMRT could reverse the action of increased levels of GRs in HeLa cells, thus indicating that the effects of cofactors on transcription may be general for GR in a variety of cells. These data further indicate that GRs are yet an additional target of the corepressor SMRT. At the same time, these cofactors were found to be capable of regulating the level of residual agonist activity displayed by antiglucocorticoids. Finally, these observations suggest that a novel role for cofactors is to participate in processes that determine the dose-response curve, and partial agonist activity, of GR-steroid complexes. This new activity of cofactors is disconnected from their ability to increase or decrease GR transactivation. An equilibrium model is proposed in which the ratio of coactivator-corepressor bound to either receptor-agonist or -antagonist complexes regulates the final transcriptional properties.
Szapary
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D
National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Molecular and Cellular Biology, National Institutes of Health, Bethesda, Maryland 20892-0805, USA.
Huang
Y
Y
Simons
S S
SS
D002460:Cell Line; D004268:DNA-Binding Proteins / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D056985:Nuclear Receptor Co-Repressor 2; D051958:Nuclear Receptor Coactivator 2; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D012097:Repressor Proteins / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000494:pharmacology*; D014162:Transfection
D004268:DNA-Binding Proteins; D005938:Glucocorticoids; C498001:NCOA2 protein, human; C539130:NCOR2 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D051958:Nuclear Receptor Coactivator 2; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D014157:Transcription Factors; D003907:Dexamethasone