Mechanisms for glucocorticoid vs. progesterone receptor-specific gene regulation

已证明辅阻遏物NCoR和SMRT对激动剂的EC 50和PAA具有相反的作用，用于相同细胞中相同基因的GR和PR诱导。 这些反向响应取决于每种受体的N-和C-末端结构域的联合作用（Song等人，2001，J. Biol. Chem.，276，24806-24816）。 这些结果与辅阻遏物与GR和PR的N-末端区域相互作用的证明一致（Wang等人，2007，Biochemistry，48，8036-8049; Wang和Simons Jr.，2005，Mol.远藤，19，1483-1500）。 类似地，最近发现已知调节GR活性的四种其他因子（GME、GMEB 2、Ubc 9和STAMP）在其他相同条件下差异性地改变GR相对于PR的几个诱导参数，或者需要每种受体的不同区域用于其活性（Szapary等人，2008，Mol Cell Endocrinol，283，114-126）。 本研究的目的是确定已知差异调节GR与PR调节基因转录的EC 50、PAA和Amax的那些因子的作用机制是否发生变化。 随着我们开发了类固醇受体作用的理论模型（见DK DK 057800 -19），这项任务才变得容易处理。 这个模型的两个新的功能，其相关的图形分析，允许一个前所未有的水平的类固醇受体调节基因反式激活的机制信息。 首先，现在可以确定因子所显示的作用类型（竞争性抑制剂、非竞争性抑制剂、共激活剂等）。 其次，通常可以定义因子相对于称为浓度限制步骤（CLS）的参考点的作用位置，浓度限制步骤是酶动力学速率限制步骤的稳态模拟。 该模型和相关的图形分析的有效性和准确性已被支持的实验观察GR。 我们现在正在将这种方法扩展到PR。 通过分析调节因素在相同条件下对GR与PR产生不同反应的后果，我们应该能够以前所未有的细节水平来辨别潜在的机制差异。 这些研究有助于我们在分子水平上确定类固醇激素的作用并了解其在人体生理学中的作用的长期目标。

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.