In vivo evidence against the existence of antiprogestins disrupting receptor binding to DNA.

The binding of a steroid hormone to its receptor elicits a sequence of events: activation of the receptor (probably through dissociation from a complex of heat shock proteins), dimerization, binding to hormone responsive elements, and finally modulation of gene transcription. RU 486, the first antiprogestin studied, has been shown to act at the last step of this sequence: provoking an inefficient binding of the receptor to hormone responsive elements. Recently, based on in vitro studies, it has been proposed that ZK 98299 was the prototype of a second class of antiprogestins that were supposed to act through disruption of the binding to DNA. We have devised methods allowing us to study the various steps of agonist or antagonist action in vivo. We show here that RU 486 and ZK 98299 have the same effects on receptor activation, dimerization, and binding to hormone responsive elements; differences in their action are explained by the 10-fold difference in their affinity for the receptor (ZK 98299 having the lower affinity). IMAGES:

类固醇激素（steroid hormone）与其受体（receptor）结合可触发一系列级联反应：受体激活（可能通过脱离热休克蛋白（heat shock proteins）复合物实现）、二聚化、结合激素应答元件（hormone responsive elements），最终调控基因转录（gene transcription）。首个被研究的抗孕激素（antiprogestin）RU 486已被证实作用于该通路的最后一步：引发受体与激素应答元件的低效结合。近期，基于体外（in vitro）研究，有研究者提出ZK 98299是第二类抗孕激素的原型，这类抗孕激素被认为通过破坏受体与DNA的结合发挥作用。我们开发了可在体内（in vivo）研究激动剂（agonist）或拮抗剂（antagonist）作用各环节的实验方法。本文结果显示，RU 486与ZK 98299对受体激活、二聚化及结合激素应答元件的作用完全一致；二者作用的差异可由其对受体的亲和力（affinity）相差10倍来解释（ZK 98299的亲和力更低）。图片：