The estrogen receptor β-isoform (ERβ) of the human estrogen receptor modulates ERα transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens
The estrogen receptor β-isoform (ERβ) of the human estrogen receptor modulates ERα transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens
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DOI：
10.1210/en.140.12.5566
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发表时间：
1999-12-01
期刊：
影响因子：
4.8
通讯作者：
McDonnell, DP
中科院分区：
文献类型：
--
作者：
Hall, JM;McDonnell, DP
人类雌激素受体α(ERα)和最近发现的ERβ具有高度的氨基酸同源性；然而，这些受体在可能影响转录活性的区域存在显著差异。因此，我们比较了这些受体调节靶基因转录的机制(S)，并评估了两种ER亚型共同表达的细胞后果。以前，已经确定ERα包含两个不同的激活结构域，ERα-AF-1和ERα-AF-2，其转录活性受细胞和启动子环境的影响。我们确定ERβ和ERα一样，含有一个功能性的AF-2，然而，ERβ-AF-2结构域在受体中独立发挥作用。另一个重要的发现是，ERβ在其氨基末端不包含强大的AF-1，而是包含一个阻遏结构域，当被移除时，会增加受体的整体转录活性。当确定ERβ在激素亚饱和水平下作为ERα转录活性的跨显性抑制因子发挥作用，并且ERβ降低细胞对雌二醇的整体敏感性时，这些发现的重要性被揭示出来。此外，在某些情况下，他莫昔芬通过ERα表现的部分激动剂活性在ERβ共表达时被完全取消。在探索ERβ介导的抑制ERα转录活性的机制时，我们已经确定：1)ERα和ERβ可以在靶细胞内形成异二聚体；2)ERβ以不依赖配体的方式与靶基因启动子相互作用。综上所述，这些数据表明，ERβ的一个作用是调节ERα的转录活性，因此这两种异构体的相对表达水平将是细胞对激动剂和拮抗剂反应的关键决定因素。
The human estrogen receptor alpha (ER alpha) and the recently identified ER beta share a high degree of amino acid homology; however, there are significant differences in regions of these receptors that would be expected to influence transcriptional activity. Consequently, we compared the mechanism(s) by which these receptors regulate target gene transcription, and evaluated the cellular consequences of coexpression of both ER subtypes. Previously, it has been determined that ER alpha contains two distinct activation domains, ER alpha-AF-1 and ER alpha-AF-2, whose transcriptional activity is influenced by cell and promoter context. We determined that ER beta, like ER alpha, contains a functional AF-2, however, the ER beta-AF-2 domain functions independently within the receptor. Of additional significance was the finding that ER beta does not contain a strong AF-1 within its amino-terminus but, rather, contains a repressor domain that when removed, increases the overall transcriptional activity of the receptor. The importance of these findings was revealed when it was determined that ER beta functions as a transdominant inhibitor of ER alpha transcriptional activity at subsaturating hormone levels and that ER beta decreases overall cellular sensitivity to estradiol. Additionally, the partial agonist activity of tamoxifen manifest through ER alpha in some contexts was completely abolished upon coexpression of ER beta. In probing the mechanisms underlying ER beta-mediated repression of ER alpha transcriptional activity we have determined that 1) ER alpha and ER beta can form heterodimers within target cells; and 2) ER beta interacts with target gene promoters in a ligand-independent manner. Cumulatively, these data indicate that one role of ER beta is to modulate ER alpha transcriptional activity, and thus the relative expression level of the two isoforms will be a key determinant of cellular responses to agonists and antagonists.