Mechanisms for glucocorticoid vs. progesterone receptor-specific gene regulation

通过我们对类固醇受体作用理论模型的开发，比较GR-与pr -调控基因转录的机制细节的任务获得了额外的标准（Ong等人，2010,Proc Natl Acad Sci U S a, 107, 7107-7112）。该模型的三个新特征及其相关的图形分析，允许关于类固醇受体调节的基因转激活的机制信息达到前所未有的水平。首先，现在可以确定因子（竞争性减速器、非竞争性减速器、加速器等）所显示的动作的动力学定义类型。其次，通常可以确定因子相对于称为浓度限制步骤（CLS）的参考点的作用位置，这是酶动力学限速步骤的稳态模拟。第三，该模型及其图形分析最近已扩展到同一试验中两个竞争因素的分析（Dougherty等人，2012,PLoS ONE, 7, e30225）。与使情况更加模糊相反，这种竞争分析实际上产生了更多的机制信息。这种竞争分析不仅可以确定每个因素相对于CLS的作用方式和作用位置，而且通常可以揭示两个因素相对于彼此的作用位置。因此，人们现在可以根据辅助因子的生物学功能组装一个有序的反应序列，就像上位分析一样，即使辅助因子的生化特性是未知的。用几个辅助因子进行的初步实验并没有暴露出GR和PR作用之间的任何主要差异。最近的实验发现了许多改变gr调控基因诱导的Amax和EC50的因素。未来的研究将确定这些新因素是否优先影响GR- vs. pr介导的反应。这些研究极大地有助于我们在分子水平上定义GRs与pr的作用，并了解它们在人体生理学中的作用。

The task of comparing the mechanistic details of GR- vs. PR-regulated gene transcription gained additional criteria with our development of a theoretical model of steroid receptor action (Ong et al., 2010, Proc Natl Acad Sci U S A, 107, 7107-7112). Three 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 kinetically-defined type of action being displayed by the factor (competitive decelerator, uncompetitive decelerator, acelerator, 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. Third, the model and its graphical analysis have recently been extended to the analysis of two competing factors in the same assay (Dougherty et al., 2012, PLoS ONE, 7, e30225). As opposed to making the situation more obscure, this competition assay actually yields greater mechanistic information. Not only can such competition assays determine how and where each factor acts, relative to the CLS, but the site of action of the two factors relative to each other is usually revealed. Thus, one can now assemble an ordered sequence of reactions based on the biological function of cofactors, much as in epistasis analysis, even when the biochemical properties of the cofactors are not known. Initial experiments with a several cofactors have not exposed any major differences between GR and PR action. Recent experiments have uncovered numerous factors that alter the Amax and EC50 of GR-regulated gene induction. Future studies will determine whether any of these new factors preferentially affect GR- vs. PR-mediated responses. These studies greatly contribute to our long-term goal of defining the action of GRs vs. PRs at a molecular level and of understanding their role in human physiology.