Altered pharmacology and distinct coactivator usage for estrogen receptor-dependent transcription through activating protein-1
Altered pharmacology and distinct coactivator usage for estrogen receptor-dependent transcription through activating protein-1
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DOI：
10.1073/pnas.0407113102
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发表时间：
2005-01-18
影响因子：
11.1
通讯作者：
Kraus, WL
中科院分区：
文献类型：
--
作者：
Cheung, E;Acevedo, ML;Kraus, WL
雌激素信号传导至少通过两种不同的分子途径发生：(i) 配体雌激素受体 (ER) 与雌激素反应性 DNA 元件 (ERE) 直接结合（“-ER/ERE 途径”）和 (h) 通过 Fos 和 Jun 的异二聚体间接招募配体 ER 来激活蛋白 1 (AP-1) 反应性 DNA 元件（“ER/AP-1 途径”）。我们开发了一种生化检测方法来检查ER/AP-1 途径中 ER 配体调节的转录通过使用各种基于细胞的测定来重现该途径中选择性雌激素受体调节剂药物的改变（即激动）药理学。我们的研究表明 (i) ERalpha/AP-1 复合物在促进稳定 RNA 聚合酶 11 的形成中发挥着关键作用。导致转录起始的预起始复合物，(ii) 染色质是 ERα/AP-1 途径中雌激素和选择性雌激素受体调节剂信号传导的关键决定因素，(iii) ERα 的不同结构域需要招募到 DNA 结合的 Fos/Jun 异二聚体并在 AP-1 位点进行转录激活，以及 (iv) ERα 和 AP-1 途径中的不同增强子/激活剂组合以不同的方式使用共激活剂。增加了我们对 ER/AP-1 途径中配体依赖性信号传导的分子机制的理解，并证明了这种生化方法的有用性。
Estrogen signaling occurs through at least two distinct molecular pathways: (i) direct binding of liganded estrogen receptors (ERs) to estrogen- responsive DNA elements (EREs) (the -ER/ERE pathway") and (h) indirect recruitment of liganded ERs to activating protein-1 (AP-1)-responsive DNA elements via heterodimers of Fos and Jun (the "ER/AP-1 pathway"). We have developed a biochemical assay for examining ligand-regulated transcription by ERs in the ER/AP-1 pathway. This assay recapitulates the altered (i.e., agonistic) pharmacology of selective estrogen receptor modulator drugs in this pathway reported previously by using various cell-based assays. We used our biochemical assay to examine the detailed mechanisms of ER/AP-1-dependent transcription. Our studies indicate that (i) ERalpha/AP-1 complexes play a critical role in promoting the formation of stable RNA polymerase 11 preinitiation complexes leading to transcription initiation, (ii) chromatin is a key determinant of estrogen and selective estrogen receptor modulator signaling in the ERalpha/AP-1 pathway, (iii) distinct domains of ERalpha are required for recruitment to DNA-bound Fos/Jun heterodimers and transcriptional activation at AP-1 sites, and (iv) different enhancer/ activator combinations in the ERalpha and AP-1 pathways use coactivators in distinct ways. These studies have increased our understanding of the molecular mechanisms underlying ligand-dependent signaling in the ER/AP-1 pathway and demonstrate the usefulness of this biochemical approach.