Estrogen response element-dependent regulation of transcriptional activation of estrogen receptors alpha and beta by coactivators and corepressors.
Estrogen response element-dependent regulation of transcriptional activation of estrogen receptors alpha and beta by coactivators and corepressors.
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发表时间：
2004
影响因子：
3.5
通讯作者：
C. Klinge;S. C. Jernigan;K. Mattingly;K. E. Risinger;J. Zhang
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文献类型：
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作者：
C. Klinge;S. C. Jernigan;K. Mattingly;K. E. Risinger;J. Zhang
配体激活的雌激素受体α和β（ER α和ER β）刺激基因转录的一种机制是通过与特定DNA序列（雌激素反应元件（ERE））的直接ER相互作用。ERE结合的ER募集刺激基因转录的共激活因子。ER与具有不同核苷酸序列的天然和合成ERE的结合改变ER结合亲和力、构象和转录活性，表明ERE序列是ER作用的变构效应物。在这里，我们测试的假设，即在ER构象的变化引起的结合不同的ERE序列调节ER与辅激活子和辅阻遏物的相互作用。用ER α或ER β转染的CHO-K1细胞显示ER α和ER β与辅激活剂类固醇受体辅激活剂1（SRC-1）、SRC-2（糖皮质激素受体相互作用蛋白1（GRIP 1））、在乳腺癌1（AIB 1）和ACTR中扩增的SRC-3、环AMP结合蛋白（CBP）和类固醇受体RNA激活剂（SRA），辅阻遏物核受体辅阻遏物（NCoR）和类维生素A和甲状腺激素受体的沉默介体（SMRT），以及次级辅激活物辅激活物相关精氨酸甲基转移酶1（CARM 1）和蛋白质精氨酸甲基转移酶1（PRMT 1）。我们注意到雌激素受体辅助调节因子活性的配体独立性以及雌二醇和4-羟基他莫昔芬依赖性差异。在体外ER-ERE结合试验中使用受体相互作用域的这些coregulators未能概括的细胞为基础的结果，证实了全长蛋白质在调节ER活性的重要性。这些数据表明，ERE序列影响雌二醇和4-羟基他莫昔芬占据ER α和ER β与辅调节因子的相互作用，如通过哺乳动物细胞中的转录活性所测量的。
One mechanism by which ligand-activated estrogen receptors alpha and beta (ERalpha and ERbeta) stimulate gene transcription is through direct ER interaction with specific DNA sequences, estrogen response elements (EREs). ERE-bound ER recruits coactivators that stimulate gene transcription. Binding of ER to natural and synthetic EREs with different nucleotide sequences alters ER binding affinity, conformation, and transcriptional activity, indicating that the ERE sequence is an allosteric effector of ER action. Here we tested the hypothesis that alterations in ER conformation induced by binding to different ERE sequences modulates ER interaction with coactivators and corepressors. CHO-K1 cells transfected with ERalpha or ERbeta show ERE sequence-dependent differences in the functional interaction of ERalpha and ERbeta with coactivators steroid receptor coactivator 1 (SRC-1), SRC-2 (glucocorticoid receptor interacting protein 1 (GRIP1)), SRC-3 amplified in breast cancer 1 (AIB1) and ACTR, cyclic AMP binding protein (CBP), and steroid receptor RNA activator (SRA), corepressors nuclear receptor co-repressor (NCoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT), and secondary coactivators coactivator associated arginine methyltransferase 1 (CARM1) and protein arginine methyltransferase 1 (PRMT1). We note both ligand-independent as well estradiol- and 4-hydroxytamoxifen-dependent differences in ER-coregulator activity. In vitro ER-ERE binding assays using receptor interaction domains of these coregulators failed to recapitulate the cell-based results, substantiating the importance of the full-length proteins in regulating ER activity. These data demonstrated that the ERE sequence impacts estradiol-and 4-hydroxytamoxifen-occupied ERalpha and ERbeta interaction with coregulators as measured by transcriptional activity in mammalian cells.