Modulation of transcriptional sensitivity of mineralocorticoid and estrogen receptors.
Recent reports describe the ability of factors to modulate the position of the dose-response curve of receptor-agonist complexes, and the amount of partial agonist activity of receptor-antagonist complexes, of androgen, glucocorticoid (GRs), and progesterone receptors (PRs). We now ask whether this modulation extends to the two remaining steroid receptors: mineralocorticoid (MRs) and estrogen receptors (ERs). These studies of MR were facilitated by our discovery that the antiglucocorticoid dexamethasone 21-mesylate (Dex-Mes) is a new antimineralocorticoid with significant amounts of partial agonist activity. Elevated levels of MR, the co-activators TIF2 and SRC-1, and the co-repressor SMRT do modulate the dose-response curve and partial agonist activity of MR complexes. Interestingly, the precise responses are indistinguishable from those seen with GRs in the same cells. Thus, the unequal transactivation of common genes by MRs versus GRs probably cannot be explained by differential responses to changing cellular concentrations of homologous receptor, co-activators, or co-repressors. We also find that the dose-response curve of ER-estradiol complexes is left-shifted to lower steroid concentrations by higher amounts of exogenous ER. Therefore, the modulation of either the dose-response curve of agonists or the partial agonist activity of antisteroid, and in many cases the modulation of both properties, is a common phenomenon for all of the classical steroid receptors.