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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Estrogen receptor (ER)-β isoforms: A key to understanding ER-β signaling
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Estrogen receptor (ER)-β isoforms: A key to understanding ER-β signaling

机译：雌激素受体（ER）-β亚型：了解ER-β信号传导的关键

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摘要

Estrogen receptor beta (ER-β) regulates diverse physiological functions in the human body. Current studies are confined to ER-β1, and the functional roles of isoforms 2, 4, and 5 remain unclear. Full-length ER-β4 and -β5 isoforms were obtained from a prostate cell line, and they exhibit differential expression in a wide variety of human tissues/cell lines. Through molecular modeling, we established that only ER-β1 has a full-length helix 11 and a helix 12 that assumes an agonist-directed position. In ER-β2, the shortened C terminus results in a disoriented helix 12 and marked shrinkage in the coactivator binding cleft. ER-β4 and -β5 completely lack helix 12. We further demonstrated that ER-β1 is the only fully functional isoform, whereas ER-β2, -β4, and -β5 do not form homodimers and have no innate activities of their own. However, the isoforms can heterodimerize with ER-β1 and enhance its transactivation in a ligand-dependent manner. ER-β1 tends to form heterodimers with other isoforms under the stimulation of estrogens but not phy-toestrogens. Collectively, these data support the premise that (ⅰ) ER-β1 is the obligatory partner of an ER-β dimer, whereas the other isoforms function as variable dimer partners with enhancer activity, and (ⅱ) a single functional helix 12 in a dimer is sufficient for gene transactivation. Thus, ER-β behaves like a noncanonical type-Ⅰ receptor, and its action may depend on differential amounts of ER-β1 homo- and heterodimers formed upon stimulation by a specific ligand. Our findings have provided previously unrecognized directions for studying ER-β signaling and design of ER-β-based therapies.
机译：雌激素受体β（ER-β）调节人体的多种生理功能。目前的研究仅限于ER-β1，异构体2、4和5的功能作用仍不清楚。全长ER-β4和-β5同工型是从前列腺细胞系中获得的，它们在多种人体组织/细胞系中表现出差异表达。通过分子建模，我们确定只有ER-β1具有全长螺旋11和呈激动剂导向位置的螺旋12。在ER-β2中，缩短的C末端导致螺旋12失去方向，并在辅助活化剂结合裂隙中明显收缩。 ER-β4和-β5完全缺少12螺旋。我们进一步证明ER-β1是唯一的全功能同工型，而ER-β2，-β4和-β5不形成同二聚体，也没有自身的先天活性。但是，这些同工型可以与ER-β1异源二聚体，并以依赖配体的方式增强其反式激活。 ER-β1在雌激素的刺激下趋于与其他同工型形成异二聚体，而在植物雌激素的刺激下趋于形成异二聚体。总的来说，这些数据支持以下前提：（ⅰ）ER-β1是ER-β二聚体的强制配偶体，而其他同工型则充当具有增强子活性的可变二聚体配偶体，和（ⅱ）二聚体中的单个功能螺旋12足以进行基因反式激活。因此，ER-β的行为类似于非经典的Ⅰ型受体，其作用可能取决于特定配体刺激后形成的ER-β1同二聚体和异二聚体的差异量。我们的发现为研究ER-β信号传导和基于ER-β的疗法的设计提供了以前无法识别的方向。

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