Mechanisms for glucocorticoid vs. progesterone receptor-specific gene regulation

已有文献记载，在同一细胞中，对于同一基因的GR和PR诱导，共抑制因子NCoR和SMRT对激动剂的EC50和PAA具有相反的影响。这些反向反应依赖于每个受体的N端和c端结构域的联合作用（Song et al., 2001， J. Biol.）。化学。， 276, 24806-24816)。这些结果与共抑制因子与gr和pr的n端相互作用的证明是一致的（Wang et al., 2007, Biochemistry, 48, 8036-8049; Wang and Simons Jr., 2005, Mol. Endo.）。， 19, 1483-1500)以及受体c端序列中最初定义的位点。类似地，最近发现了另外四个已知的调节GR活性的因子（GME、GMEB2、Ubc9和STAMP），它们要么在其他条件相同的情况下不同地改变GR和pr的几个诱导参数，要么需要每种受体的不同区域才能发挥活性（Szapary等人，2008,Mol Cell Endocrinol, 283, 114-126）。

The corepressors NCoR and SMRT have been documented to have opposite effects on the EC50 of agonists, and the PAA, 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 determine whether the mechanisms of action change for those factors known to differentially modulate the EC50, PAA, and Amax of GR- vs. PR-regulated gene transcription. This task has just become tractable with our development of a theoretical model of steroid receptor action (see DK DK057800-19). Two novel features of this model, and its associated graphical analysis, permit an unprecedented level of mechanistic information regarding steroid receptor-regulated gene transactivation. First, it is now possible to determine the type of action being displayed by the factor (competitive inhibitor, uncompetitive inhibitor, coactivator, etc.). Second, it is usually possible to define where the factor acts relative to a reference point called the concentration limiting step (CLS), which is the steady state analog of the rate limiting step of enzyme kinetics. The validity and accuracy of this model and associated graphical analyses have been supported by experimental observations for GRs. We are now extending this approach to PRs. By analyzing the consequences of modulatory factors producing different responses with GRs vs. PRs under the same conditions, we should be able to discern underlying mechanistic differences at a hitherto unparalleled level of detail. 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.