Glucocorticoid receptor cofactors as therapeutic targets

Abstract

Numerous transcriptional cofactors (e.g. coactivators, corepressors, and comodulators) are known to alter the maximal transcriptional activity (A(max)) in gene induction and repression by steroid receptors in general and glucocorticoid receptors (GRs) in particular. However, recent data advance the earlier reports that these same factors also modify other parameters of glucocorticoid receptor transcriptional activity: the potency of agonists (or EC₅₀ and the partial agonist activity of antisteroids (or PAA). In several instances, factors modulate the EC₅₀ and/or PAA without changing A(max). Thus, studies of all three parameters reveal new factors acting at various stages of receptor action, thereby increasing the potential therapeutic targets for adjusting GR actions in pathological situations.

Fig. 1

Diagramatic cartoon of steps in steroid hormone action that can result in an FHDC and are potential therapeutic targets. For simplicity, not all currently proposed steps are shown and no attempt has been made to identify which steps are reversible/cycling or irreversible. The steroid (S) binds to receptor (R), which then binds to DNA to give RS-DNA complexes. Various cofactors (e.g., A, B, …, U) can participate in the eventual production of mRNA product, which is then translated into protein. Some point in the reaction sequence could contain a concentration limiting step (CLS). The functional significance of the CLS is that the amount of any bound factor after the CLS is very small, so that the free concentration of factor is essentially equal to its total concentration. Under appropriate conditions, each step/cofactor can alter the maximal activity (A_max) and/or potency (EC₅₀) and is thus a potential target of therapeutic intervention [from ref. 58]. It is possible that most, if not all, steps are also be able to modulate the partial agonist activity (PAA) of antisteroids.