PROGESTERONE-RECEPTOR AND THE MECHANISM OF ACTION OF PROGESTERONE ANTAGONISTS
PROGESTERONE-RECEPTOR AND THE MECHANISM OF ACTION OF PROGESTERONE ANTAGONISTS
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DOI：
10.1016/0960-0760(95)00091-d
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发表时间：
1995-06-01
影响因子：
4.1
通讯作者：
BECK, CA
中科院分区：
文献类型：
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作者：
EDWARDS, DP;ALTMANN, M;BECK, CA
目前可用的孕酮拮抗剂已被建议分为两类，基于它们如何与孕酮受体（PR）相互作用和抑制孕酮受体（PR）的差异。抗-白蛋白ZK 98299（I型）损害PR与DNA的结合，而II型化合物（RU 486、ZK 112993、ZK 98734）促进PR与DNA的结合。因此，II型药物似乎在DNA结合的下游步骤抑制受体活性，推测未能诱导增强转录所需的PR结构的构象变化。本文讨论了已发表和未发表的数据支持的概念，两种类型的resistin拮抗剂。使用PR介导的乳腺癌细胞中的报告基因的诱导作为生物反应的测定，两种类型的抗孕激素，校正类固醇结合亲和力的差异后，亚化学计量地抑制孕激素诱导。然而，II型抗孕激素更有效，在比ZK 98299更低的拮抗剂与激动剂比率下抑制。这表明，除了通过经典的竞争性机制起作用之外，这些化合物（特别是II型）可以在与激素激动剂结合的相同细胞中表现出作为PR的反式阻遏物的额外活性。反式阻遏可以通过异源二聚化和竞争结合DNA的组合机制发生。为了支持这一点，混合配体二聚体在溶液中容易地在结合激动剂的PR亚基和结合任一类型的抗孕酮的另一个PR亚基之间形成，而这些混合配体二聚体在体外与特异性孕酮反应元件（PRE）结合很差（如果有的话）。此外，当作为单一配体添加时，与由胰蛋白酶激动剂形成的单一配体二聚体相比，II型试剂增加溶液中的PR二聚化和PR对PRE的亲和力。这与ZK 98299形成对比，当作为单一配体给予时，ZK 98299降低PR对PRE的亲和力而不破坏溶液二聚化。因此，与ZK 98299相比，PR对PRE的更高亲和力可以解释II型化合物更大的生物学效力。作为抗孕激素类型之间的进一步区别，ZK 98299最低限度地刺激PR的磷酸化，而RU 486以与激素激动剂难以区分的方式增加PR的位点特异性磷酸化。此外，ZK 98299在体内不容易通过与cAMP信号转导途径的串扰而功能转换为部分激动剂，正如II型化合物所发生的那样。因此，在某些条件下，ZK 98299可能是比II型化合物更纯的拮抗剂。
Currently available progesterone antagonists have been suggested to fall into two categories based on differences in how they interact with and inactivate the progesterone receptor (PR). The anti-progestin ZK98299 (Type I) impairs PR association with DNA, while Type II compounds (RU486, ZK112993, ZK98734) promote PR binding to DNA. Type II agents, therefore, appear to inhibit receptor activity at a step downstream of DNA binding, presumably failing to induce conformational changes in PR structure required for enhancement of transcription. This paper discusses both published and unpublished data supporting the concept of two types of progestin antagonists. Using PR-mediated induction of reporter genes in breast cancer cells as an assay for biological response, both types of anti-progestins, after correction for difference in steroid binding affinity, inhibit progestin induction substoichiometrically. However, Type II anti-progestins are more potent, inhibiting at lower ratios of antagonist to agonist than ZK98299. This suggests that in addition to behaving by classical competitive mechanisms these compounds (in particular Type II) may exhibit additional activity as transrepressors of PR in the same cell bound to hormone agonist. Transrepression may occur by the combined mechanisms of heterodimerization and competition for binding to DNA. In support of this, mixed ligand dimers form readily in solution between a PR subunit bound to agonist and another bound to either type of anti-progestin, whereas these mixed ligand dimers bind poorly, if at all, to specific progesterone response elements (PREs) in vitro. Additionally, when added as a single ligand, Type II agents increase PR dimerization in solution and PR affinity for PREs as compared with single ligand dimers formed by progestin agonist. This contrasts with ZK98299, when given as a single ligand, which reduces PR affinity for PREs without disrupting solution dimerization. Thus the higher affinity of PR for PREs may account for the greater biological potency of Type II compounds as compared with ZK98299. As a further distinction between types of antiprogestins, ZK98299 minimally stimulates phosphorylation of PR whereas RU486 increases site-specific phosphorylation of PR in a manner indistinguishable from that of hormone agonist. Additionally, ZK98299 is not susceptible in vivo to functional switching to a partial agonist by cross talk with cAMP signal transduction pathways, as occurs with Type II compounds. Thus, ZK98299 under certain conditions may be a more pure antagonist than Type II compounds.