Effects of acetylation, polymerase phosphorylation, and DNA unwinding in glucocorticoid receptor transactivation.
Effects of acetylation, polymerase phosphorylation, and DNA unwinding in glucocorticoid receptor transactivation.
复制标题
乙酰化、聚合酶磷酸化和 DNA 解旋对糖皮质激素受体反式激活的影响。
DOI：
10.1016/j.jsbmb.2006.03.003
复制
发表时间：
2006
期刊：
影响因子：
--
通讯作者：
SimonsJr,SStoney
中科院分区：
文献类型：
--
作者：
Kim,Yuli;Sun,Yunguang;Chow,Carson;Pommier,YvesG;SimonsJr,SStoney
通过改变剂量-反应曲线的位置(或半最大诱导值=EC50)和抗类固醇的部分激动剂活性的量，改变选定因子的浓度来改变类固醇受体的诱导特性。我们现在描述一个基本的数学模型，该模型预测类固醇调节基因诱导的多步骤过程的简单米氏曲线。这一模型表明，从受体结合到类固醇的下游步骤可以影响激动剂-复合体的EC50和拮抗剂-复合体的部分激动剂活性。因此，我们询问了三个可能的下游步骤的抑制剂是否可以逆转两种因素浓度增加的影响：糖皮质激素受体(GRs)和Ubc9。下游步骤(括号中有抑制剂)是蛋白质去乙酰化(TSA和VPA)、DNA解旋(CPT)和RNA聚合酶II(DRB和H8)的CTD磷酸化。没有一种抑制剂模仿或阻止添加的GRs的影响。然而，DNA解旋和CTD磷酸化的抑制剂确实逆转了高浓度GR的Ubc9的作用。这些结果支持我们早先的结论，即不同的限速步骤在低浓度和高GR浓度下与Ubc9的高GR浓度下起作用。目前的数据还表明，下游步骤可以调节GR介导的诱导的EC50，从而支持我们的数学模型的实用性，并拓宽了可以修改EC50的生化过程的领域。
Varying the concentration of selected factors alters the induction properties of steroid receptors by changing the position of the dose–response curve (or the value for half-maximal induction=EC50) and the amount of partial agonist activity of antisteroids. We now describe a rudimentary mathematical model that predicts a simple Michaelis–Menten curve for the multi-step process of steroid-regulated gene induction. This model suggests that steps far downstream from receptor binding to steroid can influence the EC50of agonist-complexes and partial agonist activity of antagonist-complexes. We therefore asked whether inhibitors of three possible downstream steps can reverse the effects of increased concentrations of two factors: glucocorticoid receptors (GRs) and Ubc9. The downstream steps (with inhibitors in parentheses) are protein deacetylation (TSA and VPA), DNA unwinding (CPT), and CTD phosphorylation of RNA polymerase II (DRB and H8). None of the inhibitors mimic or prevent the effects of added GRs. However, inhibitors of DNA unwinding and CTD phosphorylation do reverse the effects of Ubc9 with high GR concentrations. These results support our earlier conclusion that different rate-limiting steps operate at low and high GR concentrations versus high GR with Ubc9. The present data also suggest that downstream steps can modulate the EC50of GR-mediated induction, thus both supporting the utility of our mathematical model and widening the field of biochemical processes that can modify the EC50.