Modulation of transcription parameters in glucocorticoid receptor-mediated repression.

Glucocorticoid receptors (GRs) affect both gene induction and gene repression. The disparities of receptor binding to DNA and increased vs. decreased gene expression have suggested significant mechanistic differences between GR-mediated induction and repression. Numerous transcription factors are known to modulate three parameters of gene induction: the total activity (Vmax) and position of the dose-response curve with glucocorticoids (EC50) and the percent partial agonist activity with antiglucocorticoids. We have examined the effects on GR-mediated repression of five modulators (coactivators TIF2 [GRIP1, SRC-2] and SRC-1, corepressor SMRT, and comodulators STAMP and Ubc9), a glucocorticoid steroid (deacylcortivazol [DAC]) of very different structure, and an inhibitor of histone deacetylation (trichostatin A [TSA]). These factors interact with different domains of GR and thus are sensitive topological probes of GR action. These agents altered the Vmax, EC50, and percent partial agonist activity of endogenous and exogenous repressed genes similarly to that previously observed for GR-regulated gene induction. Collectively, these results suggest that GR-mediated induction and repression share many of the same molecular interactions and that the causes for different levels of gene transcription arise from more distal downstream steps.

Differential modulation of glucocorticoid and progesterone receptor transactivation.

The determinants of the different biological activities of progesterone receptors (PRs) vs. glucocorticoid receptors (GRs), which bind to the same DNA sequences, remain poorly understood. The mechanisms by which differential expression of a common target gene can be achieved by PR and GR include unequal agonist steroid concentrations for half maximal induction (EC50) and dissimilar amounts of residual partial agonist activity for antisteroids in addition to the more common changes in total gene induction, or Vmax. Several factors are known to alter some or all of these three parameters for GR-regulated gene induction and some (i.e., the corepressors NCoR and SMRT) modulate the EC50 and partial agonist activity for GR and PR induction of the same gene in opposite directions. The current study demonstrates that other factors known to modulate GR properties (GME, GMEB-2, Ubc9, and STAMP) can also differentially interact with PRs or alter several of the above induction parameters under otherwise identical conditions. These results support the hypothesis that the modulation of EC50, partial agonist activity, and Vmax by a given factor is not limited to one receptor in a specific cell line. Furthermore, the number of factors that unequally modulate PR and GR induction parameters is now greatly expanded, thereby increasing the possible mechanisms for differential gene regulation by PRs vs. GRs.