Expanding the Paradigm for Estrogen Receptor Binding and Transcriptional Activation
Expanding the Paradigm for Estrogen Receptor Binding and Transcriptional Activation
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DOI：
10.1210/me.2010-0302
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发表时间：
2011-06-01
影响因子：
--
通讯作者：
Scovell, W. M.
中科院分区：
文献类型：
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作者：
Joshi, S. R.;Ghattamaneni, R. B.;Scovell, W. M.
雌激素受体（ER）与人类基因组内的一系列功能性雌激素反应元件（ERE）结合，包括ERE半位点（HERE）、反向和正向重复序列。这是令人困惑的，因为据报道，ER在体外与这些位点的结合很弱（如果有的话）。我们表明ER与这些非传统ERE强烈结合，并且高迁移率族蛋白B1（HMGB 1）的存在增强了这种结合。总的来说，这些和以前的研究结果加强了强ER/ERE相互作用的可塑性的概念，与其更广泛的观察到的结合特异性一致。此外，使用荧光素酶报告基因测定的瞬时转染研究表明，这些ERE驱动荧光素酶活性，并且HMGB 1增强转录活性。此外，HMGB 1基因表达敲除导致荧光素酶活性急剧下降，表明HMGB 1在雌激素/ER应答基因的激活中起重要作用。因此，这些数据主张ER的最小靶位点是在许多不同情况下发生的cHERE（共识HERE），并且HMGB 1增强结合亲和力和转录活性。这对ER结合亲和力和功能活性的当前范例提出了挑战，并表明该范例需要进行重大的重新评估和修改。这些发现也表明了一个可能的机制，由ER和II类核受体调控的基因之间的串扰。（分子内分泌学25：980-994，2011）
Estrogen receptor (ER) binds to a spectrum of functional estrogen response elements (ERE) within the human genome, including ERE half-sites (HERE), inverted and direct repeats. This has been confounding, because ER has been reported to bind weakly, if at all, to these sites in vitro. We show that ER binds strongly to these nonconventional EREs, and the binding is enhanced by the presence of high-mobility group protein B1 (HMGB1). Collectively, these and previous findings reinforce the notion of the plasticity of strong ER/ERE interactions, consistent with their broader range of observed binding specificity. In addition, transient transfection studies using luciferase reporter gene assays show that these EREs drive luciferase activity, and HMGB1 enhances transcriptional activity. Furthermore, HMGB1 gene expression knockdown results in a precipitous drop in luciferase activity, suggesting a prominent role for HMGB1 in activation of estrogen/ER-responsive genes. Therefore, these data advocate that the minimal target site for ER is a cHERE (consensus HERE) that occurs in many different contexts and that HMGB1 enhances both the binding affinity and transcriptional activity. This challenges the current paradigm for ER binding affinity and functional activity and suggests that the paradigm requires significant reevaluation and modification. These findings also suggest a possible mechanism for a cross talk between genes regulated by ER and class II nuclear receptors. (Molecular Endocrinology 25: 980-994, 2011)