Truss M, Bartsch J, Beato M
Institut für Molekularbiologie und Tumorforschung, Philipps-Universität Marburg, Germany.
Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11333-7. doi: 10.1073/pnas.91.24.11333.
Antiprogestins inhibit progesterone action by competing for binding to the progesterone receptor and are potentially important pharmaceuticals in fertility control and cancer therapy. Why the complex of antiprogestins and progesterone receptor is functionally inactive is unclear. Present models are based on indirect evidence, such as transfection competition assays and in vitro DNA binding studies, partly because of difficulties in visualizing the receptor bound to DNA in vivo. Here we used genomic footprinting analysis to show ligand-dependent binding of endogenous progesterone receptor to the hormone responsive elements (HREs) of a chromosomally integrated mouse mammary tumor virus long terminal repeat in a human mammary carcinoma cell line. The antiprogestins RU 486 and ZK 98299 do not promote binding of the progesterone receptor to this natural HRE in vivo, even at concentrations that completely inhibit the agonistic effects of potent synthetic progestins. Moreover, antiprogestins cause a rapid disappearance of the agonist-induced progesterone receptor footprint. We conclude that antiprogestins interfere with receptor function by preventing its specific DNA binding.
抗孕激素通过竞争结合孕激素受体来抑制孕激素的作用，并且在生育控制和癌症治疗中可能是重要的药物。抗孕激素与孕激素受体的复合物为何在功能上无活性尚不清楚。目前的模型基于间接证据，如转染竞争试验和体外DNA结合研究，部分原因是在体内观察与DNA结合的受体存在困难。在这里，我们使用基因组足迹分析来显示内源性孕激素受体在人乳腺癌细胞系中与染色体整合的小鼠乳腺肿瘤病毒长末端重复序列的激素反应元件（HREs）的配体依赖性结合。抗孕激素RU 486和ZK 98299在体内不会促进孕激素受体与这种天然HRE的结合，即使在完全抑制强效合成孕激素激动作用的浓度下也是如此。此外，抗孕激素会导致激动剂诱导的孕激素受体足迹迅速消失。我们得出结论，抗孕激素通过阻止其特异性DNA结合来干扰受体功能。
