Estrogen receptor β acts as a dominant regulator of estrogen signaling
Estrogen receptor β acts as a dominant regulator of estrogen signaling
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DOI：
10.1038/sj.onc.1203828
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发表时间：
2000-10-12
期刊：
影响因子：
8
通讯作者：
Gustafsson, JÅ
中科院分区：
文献类型：
--
作者：
Pettersson, K;Delaunay, F;Gustafsson, JÅ
雌激素的生理作用由两种细胞内转录因子--雌激素受体（ER）介导，其通过与特异性DNA靶序列结合来调节靶基因的转录。在这里，我们描述了不同的ER激动剂和抗雌激素化合物他莫昔芬的细胞反应的改变，导致在瞬时共转染实验中的两个ER的共表达。我们的研究结果表明，ER β可以作为ER活性的负或正显性调节剂。这表现在低浓度雌二醇（E-2）时转录活性降低，三苯氧胺对E-2刺激活性的拮抗作用增加，和增强的植物雌激素化合物染料木黄酮的激动作用。此外，使用缺乏N-末端活化功能1（AF-1）的嵌合蛋白，我们表明ER α和ER β对不同激动剂和拮抗剂的不同反应主要由受体C-末端配体结合域的固有差异决定，而转录活性的大小受ER α AF-1的影响，而不受ER β AF-1的影响。ER α AF-1活性似乎在两种ER的共表达时受到调节。由ER α和ER β的共表达引起的转录活性的改变可能是由于α/β异二聚体复合物的形成，这项研究表明，ER α和ER β的共定位和随后的异源二聚体化可能导致受体活性不同于ER同源二聚体。
The physiological effects of estrogens are mediated by two intracellular transcription factors, the estrogen receptors (ERs), that regulate transcription of target genes through binding to specific DNA target sequences. Here we describe alterations in cellular responses to different ER agonists and to the anti-estrogenic compound tamoxifen resulting from co-expression of the two ERs in transient co-transfection experiments. Our results demonstrate that ER beta can act as a negative or positive dominant regulator of ER activity. This is manifested through reduced transcriptional activity at low concentrations of estradiol (E-2); increased antagonistic effects of tamoxifen on E-2 stimulated activity; and enhanced agonistic action of the phytoestrogenic compound genistein, Furthermore, using chimeric proteins lacking the N-terminal activation function 1 (AF-1), we show that the differential responses of ER alpha and ER beta to different agonists and antagonists are primarily dictated by inherent differences in the C-terminal ligand-binding domains of the receptors, whereas the magnitude of transcriptional activity is influenced by ER alpha AF-1, but not ER beta AF-1, The ER alpha AF-1 activity appears to be modulated upon co-expression of both ERs, The alterations in transcriptional activity resulting from co-expression of ER alpha and ER beta are probably due to the formation of alpha/beta heterodimeric complexes, This study demonstrates that co-localization and subsequent heterodimerization of ER alpha and ER beta may result in receptor activity distinct from that of ER homodimers.