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首页> 外文期刊>Molecular and Cellular Biology >Dominant Activity of Activation Function 1 (AF-1) and Differential Stoichiometric Requirements for AF-1 and -2 in the Estrogen Receptor α-β Heterodimeric Complex
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Dominant Activity of Activation Function 1 (AF-1) and Differential Stoichiometric Requirements for AF-1 and -2 in the Estrogen Receptor α-β Heterodimeric Complex

机译：雌激素受体α-β异二聚体复合物中活化功能1（AF-1）的主要活性以及AF-1和-2的化学计量要求。

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Estrogenic responses are now known to be mediated by two forms of estrogen receptors (ER), ERα and ERβ, that can function as homodimers or heterodimers. As homodimers the two have been recently shown to exhibit distinct transcriptional responses to estradiol (E2), antiestrogens, and coactivators, suggesting that the ER complexes are not functionally equivalent. However, because the three possible configurations of ER complexes all recognize the same estrogen response element, it has not been possible to evaluate the transcriptional properties of the ER heterodimer complex by transfection assays. Using ER subunits with modified DNA recognition specificity, we were able to measure the transcriptional properties of ERα-ERβ heterodimers in transfected cells without interference from the two ER homodimer complexes. We first demonstrated that the individual activation function 1 (AF-1) domains act in a dominant manner within the ERα-ERβ heterodimer: the mixed agonist-antagonist 4-hydroxytamoxifen acts as an agonist in a promoter- and cell context-dependent manner via the ERα AF-1, while activation of the complex by the mitogen-activated protein kinase (MAPK) pathway requires only the ERα- or ERβ-responsive MAPK site. Using ligand-binding and AF-2-defective mutants, we further demonstrated that while the ERα-ERβ heterodimer can be activated when only one E2-binding competent partner is present per dimer, two functional AF-2 domains are required for transcriptional activity. Taken together, the results of this study of a retinoid X receptor-independent heterodimer complex, the first such study, provide evidence of different stoichiometric requirements for AF-1 and -2 activity and demonstrate that AF-1 receptor-specific properties are maintained within the ERα-ERβ heterodimer.
机译：现在已知雌激素反应是由两种形式的雌激素受体（ER）ERα和ERβ介导的，它们可以充当同二聚体或异二聚体。作为同型二聚体，最近已显示二者对雌二醇（E 2 ），抗雌激素和共激活剂表现出不同的转录反应，表明ER复合物在功能上不相同。但是，由于ER复合物的三种可能构型都识别相同的雌激素响应元件，因此不可能通过转染测定来评估ER异二聚体复合物的转录特性。使用具有修饰的DNA识别特异性的ER亚基，我们能够测量转染细胞中ERα-ERβ异二聚体的转录特性，而不受两种ER同二聚体复合物的干扰。我们首先证明了单个激活功能1（AF-1）域在ERα-ERβ异二聚体中以显性方式起作用：混合的激动剂-拮抗剂4-羟基他莫昔芬通过以下方式以启动子和细胞上下文依赖性方式充当激动剂： ERαAF-1可以通过有丝分裂原激活的蛋白激酶（MAPK）途径激活复合物，而只需要ERα或ERβ响应性MAPK位点。使用配体结合和AF-2-缺陷型突变体，我们进一步证明，当每个二聚体仅存在一个与E 2 结合的配偶体时，可以激活ERα-ERβ异二聚体，而两个功能性AF-转录活性需要2个域。总而言之，这项关于类视黄醇X受体独立的异二聚体复合物的研究结果（这是首次此类研究）提供了AF-1和-2活性不同化学计量要求的证据，并证明了AF-1受体特有的特性得以维持。 ERα-ERβ异二聚体。

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