The corepressors NCoR and SMRT have been documented to have opposite effects on the EC50 of agonists, and the amount of residual agonist activity of antagonists, for GR and PR induction of the same gene in the same cells. These inverted responses depend upon the joint actions of the N- and C-terminal domains of each receptor (Song et al., 2001, J. Biol. Chem., 276, 24806-24816). These results are consistent with the demonstration that corepressors interact with N-terminal regions of both GRs and PRs (Wang et al., 2007, Biochemistry, 48, 8036-8049;Wang and Simons Jr., 2005, Mol. Endo., 19, 1483-1500) in addition to the initially defined sites in the C-terminal sequences of receptors. Similarly, four other factors known to modulate GR activity (GME, GMEB2, Ubc9, and STAMP) were recently found either to differentially alter several induction parameters of GRs vs. PRs under otherwise identical conditions or to require different regions of each receptor for their activities (Szapary et al., 2008, Mol Cell Endocrinol, 283, 114-126). The objective of this study is to examine the consequences of other factors known to modulate the EC50, percent partial agonist activity, and Amax of transiently transfected GR vs. PR complexes to further define the parameters responsible for the different biological actions of GRs and PRs. Whole cells bioassays are currently being used to determine the modulatory activity of two new modulatory factors, while ChIP assays are being performed to discern whether the presence of these factors alters the recruitment of several common transcription factors to relevant regions of endogenous regulated genes. When these studies are completed, we will perform similar experiments with PRs to identify similar and divergent molecular actions. These studies contribute to our long-term goal of defining the action of steroid hormones at a molecular level and of understanding their role in human physiology.
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