雌激素受体信号通路新进展

雌激素通过直接与两类核内雌激素受体ERα和ERβ结合,活化靶基因的转录,这是经典的雌激素受体信号转导途径。近来发现,雌激素受体还能够通过依赖或不依赖雌激素的方式与胞内一些信号通路对话,使自身被磷酸化而活化;雌激素受体还能与其它转录因子相互作用,调节自身或者其它转录因子的活化功能,参与ER阳性细胞的增殖调节。此外,雌激素能通过细胞膜上的雌激素受体进行信号转导,引起靶细胞的快速反应及活化靶基因转录,参与骨和心血管保护。     

雌激素受体β与乳腺癌

雌激素受体β(ERβ)与雌激素受体α(ERα)的结构相似,是一类配体调节的转录因子,属于核受体超家族,分布于乳腺等多种组织中,具有重要的生理病理学意义。本文简要综述雌激素受体β的基因结构、剪接变体、转录调节机制及其在乳腺癌发生发展、治疗预后和抗雌激素耐受中的意义。     

雌激素受体ERα的功能调控及相关疾病的研究进展

雌激素受体(estrogen receptorα,ERα)是依赖配体活化转录因子的核受体家族成员之一,参与靶细胞的增殖和分化。ERα活化的经典途径是与雌激素结合后直接作用于靶基因上游的雌激素受体反应元件(ERE),从而诱导靶基因转录。雌激素受体的功能受许多因子调节,包括与之结合的配体、DNA上的顺式元件、募集的辅助调节因子及细胞环境等。在雌激素受体相关疾病中,除乳腺癌和子宫内膜癌外,近年研究表明心血管疾病、骨质疏松症、阿尔茨海默氏病等疾病也与雌激素受体密切相关。雌激素的生物效应与多种疾病的发生、转归和预后密切相关。本文将综述几类辅助调节因子对雌激素受体介导的基因转录的调控,雌激素受体相关疾病,及环境有害物质对ERα功能的影响。     

雌激素受体的结构与功能

人的雌激素受体根据其氨基酸顺序的保守性可以分成6个区,其中最富于保守性的是DNA结合区和激素结合区。DNA结合区负责与专一的DNA顺序结合。激素结合区不仅能与配体(雌激素)结合,参与形成二聚体,而且具有激活靶基因转录活动等重要动能。雌激素受体蛋白-激素复合物可以被认为是一个受配体诱导的转录因子,它与具有增强子功能的DNA顺序结合后调节靶基因的转录活动。     

PNRC1剪接变异体的鉴定及其在辅激活核受体介导基因转录功能上的比较

为分析富含脯氨酸核受体辅调节蛋白1(PNRC1)选择性剪接, 及比较PNRC1剪接变异体在辅激活核受体介导基因转录功能上的差异,在生物信息学方法分析PNRC1剪接变异体的基础上,设计一定的特异性引物,采用RT-PCR结合克隆测序的方法对这些剪接变异体进行验证. 利用酵母双杂交和荧光素酶报告系统实验,分析它们与核受体的相互作用及比较它们在辅激活核受体介导基因转录功能上的差异.结果显示,生物信息学预测的几个剪接变异体真实存在于人的组织和细胞系中,这些剪接变异体在与雌激素受体α(ERα)、类固醇衍生因子1(SF1)等核受体的相互作用的强度及辅激活核受体介导基因转录功能上存在较大的差异. 研究提示,PNRC1这些剪接变异体在体内可能发挥不同的功能.     

人乳腺癌雌激素受体协调激活因子ERIAP生物学功能鉴定

雌激素受体(ER)属于核激素受体(NR)家族成员, 是一种雌激素依赖性转录因子, 在乳腺癌的发生、发展和治疗中起重要作用. 协调转录因子(协调激活因子和协调抑制因子)在ER转导激素和代谢信号到靶基因时起着关键作用. 功能和结构研究阐明, 协调激活因子通过一个和数个LXXLL基因序列(X为任意氨基酸, L为亮氨酸, 也称NR盒)与ER受体上的激受诱导活化区域相互作用. 采用酵母双杂交系统, 确定了一种与ER-α相互作用的新蛋白质ERIAP(estrogen receptor-interacting and activating protein, 雌激素受体相互作用和活化蛋白), 该蛋白质含有两个LXXLL基因序列. 通过体内免疫沉淀和体外GST捕获方法分析, 证明ERIAP以雌激素依赖性方式与ER-α相结合. ERIAP蛋白中的两个NR盒对其与ER-α相互作用是必要的. 此外, ERIAP特异性提高雌激素诱导的ER-α转录活性, 并增强雌激素响应基因pS2的表达. 研究表明, ERIAP作为一新的ER-α转录活性协调激活因子, 可能在乳腺癌的发生和发展中发挥重要的作用.     

ERα的辅调节因子与乳腺癌关系的研究进展

雌激素受体α（estrogen receptorα,ERα）是配体依赖的转录因子,属于核受体超家族成员。ERα介导转录的经典途径是与雌激素结合后作用于靶基因启动子区的雌激素反应元件（estrogen response element,ERE）,进而诱导靶基因转录。ERα招募辅调节因子（共激活子和共抑制子）参与ERα介导的基因转录调控。辅调节因子主要通过乙酰化、磷酸化、甲基化等表观遗传机制参与转录调控,影响靶蛋白表达水平。ΕRα介导的基因转录调控在乳腺癌的增殖、分化、侵袭转移等过程中发挥重要作用。综述在ERα介导的基因转录调控中几类辅调节因子对乳腺癌发生发展的影响。     

雌激素受体与神经系统疾病

雌激素受体是类固醇激素受体超家族成员之一,是一种配体依赖性转录因子,具有广泛的生物学功能。雌激素受体在脑内具有广泛的分布,且与一些神经系统疾病的发生发展相关。就雌激素受体在脑内的分布及其与神经系统疾病的关系进行论述。     

芳香烃受体核转位蛋白的结构及相关功能

芳香烃受体核转位蛋白（aryl hydrocarbon receptor nuclear translocator,ARNT）是碱性螺旋-环．螺旋转录因子超家族中新发现的PAS亚家族的成员之一。它是体内许多bHLH-PAS蛋白共同的专性配偶体,可以与芳香烃受体、低氧诱导因子、果蝇SIM蛋白等形成异二聚体并介导许多信号转导过程,从而使个体对环境污染物（如二恶英）、低氧状态等外界因素的改变产生相应的生物学效应,本文就ARNT的基本结构及其在体内的主要生理功能等方面作一综述。     

羟泰米酚的抗着床作用及其对小鼠子宫雌二醇和孕酮受体含量的影响

经雌激素拮抗剂－羟泰米酚处理后的怀孕小鼠,胚泡着床受到明显抑制;同时,着床前子宫细 胞质雌二醇受体和孕酮受体明显减少,细胞核受体明显增加;拮抗剂还使血清雌激素和孕酮含量显 著降低。结果表明：羟泰米酚的抗着床作用效应与子宫雌二醇受体和孕酮受体的正常功能受到干扰 可能是有密切关系的。     

Monitoring Endocrine Disrupter Compounds in the Tunisian Hamdoun River using In Vitro Bioassays

Anthropogenic chemicals occurring in the environment, namely endocrine-disrupting chemicals (EDCs), have generated growing concern over their potential adverse effects on human wildlife health and ecosystem processes. This interest resulted particularly from their abilities to mimic the effect of endogenous hormones. In this study, we used stable transfected reporter cell lines to investigate the endocrine-disrupting profile of water as well as sediment samples. Samples are collected from up- and downstream of an industrial wastewater discharge point at the Hamdoun River in the vicinity of an industrial zone located at the center of Tunisia. The analysis of estrogen, androgen, and xenobiotic (pregnane X and dioxin) ligands receptors expressed by chimeric cell lines indicated that while the water and sediment samples from upstream sites have lower levels of estrogenic activity, those from downstream exhibited stronger estrogenic, aryl hydrocarbon receptor (AhR), and Pregnane X Receptor (PXR) activities. Moreover, collected samples have shown hormonal activity in terms of all tested receptors except the androgenic ones. In vitro recombinant estrogen receptor competitive binding assays revealed that while the estrogenic activities of the downstream water sample compounds had a strong affinity for estrogen receptor α (ERα), those present in the sediment samples showed a weaker one. These findings were consolidated by subsequent chemical analysis (high-performance liquid chromatography with UV detectors). Our results indicate that the water and sediment discharges at the Hamdoun River represent a major sink for EDCs from natural and industrial effluents, particularly those of the textile industry, with pernicious potential to disrupt normal endocrine functions.     

雌激素信号通路概述

过去几十年,人们一直认为雌激素信号通路是雌激素与细胞核中的雌激素受体(ER)结合,作用于雌激素受体反应元件调节基因表达,从而改变细胞功能。雌激素不但与核ER结合,也能与膜ER结合激活PI3K信号通路。G蛋白偶联受体(GPR30)也能与雌激素结合,激活PI3K信号通路。雌激素通过结合不同雌激素受体改变细胞生理功能。我们对雌激素信号通路做简要综述。     

Modeling the estrogen receptor to growth factor receptor signaling switch in human breast cancer cells

Breast cancer cells develop resistance to endocrine therapies by shifting between estrogen receptor (ER)-regulated and growth factor receptor (GFR)-regulated survival signaling pathways. To study this switch, we propose a mathematical model of crosstalk between these pathways. The model explains why MCF7 sub-clones transfected with HER2 or EGFR show three GFR-distribution patterns, and why the bimodal distribution pattern can be reversibly modulated by estrogen. The model illustrates how transient overexpression of ER activates GFR signaling and promotes estrogen-independent growth. Understanding this survival-signaling switch can help in the design of future therapies to overcome resistance in breast cancer.     

Development of a stable dual cell-line GFP expression system to study estrogenic endocrine disruptors

Environmental estrogenic endocrine disruptors are a health concern. Here we constructed a dual cell-line green fluorescence protein (GFP) expression system to identify and study endocrine disrupting compounds with activities of estrogen receptor agonists or antagonists. Human breast cancer MCF-7 cells and endometrial carcinoma Ishikawa cells were infected with a two tandem estrogen response elements--E4 promoter-GFP reporter gene construct. The use of GFP reporter enabled direct and simple evaluations of cell responses. GFP intensity in stably transfected MCF7-GFP and Ishikawa-GFP cells was dose-responsive to 17-beta-estradiol, diethylstilbestrol, 2-hydroxyestradiol, and environmental toxins bisphenol A, genistein and o-p'-DDT. Raloxifene and tamoxifen were effective antiestrogens in MCF7-GFP cells, but acted as partial estrogen receptor agonists in Ishikawa-GFP cells at concentrations of 0.1 nM and above. No synergistic effect was observed in chemical combinations between organochlorine pesticides methoxychlor, o-p'-DDT, p-p'-DDT, nor between estradiol and estrone. In summary, for the first time the effects of estrogen receptor agonists or antagonists were compared between mammary and endometrial cancer cells both stably expressing identical plasmids with GFP reporter genes under the control of tandem estrogen response elements. This dual cell-line system provides a rapid method and sensitive assay to identify environmental estrogens, antiestrogens, selective estrogen receptor modulators and to study their tissue specific effects and chemical interactions. Such a system is especially useful for direct and parallel toxicity assessments with a microfluidic cell culture device.     

Aromatase inhibitors: future directions

Estrogen and its cognate estrogen receptor are key players in the etiology and progression of breast cancer. Aromatase inhibitors, suppressing tumor and plasma estrogen levels by blocking testosterone conversion to estrogen, have been proven to provide the most effective endocrine therapy for postmenopausal breast cancer patients. Aromatase inhibitors are now the first choice endocrine therapy in the metastatic setting for postmenopausal women. These endocrine agents also seem likely to soon become the standard adjuvant therapy, either alone or in sequence with tamoxifen, though their long-term toxicity and the optimum duration of therapy still remain to be defined. Advanced experimental studies and some clinical observations reveal the importance of blocking both the genomic and non-genomic activities of the estrogen receptor, as well as its crosstalk with growth factor and other cellular signaling, for greatest effectiveness of endocrine therapy. Consequently, these studies provide a mechanistic explanation for the superb performance of aromatase inhibitors, and also suggest how inhibiting selected growth factor receptors might delay or prevent the onset of resistance to aromatase inhibitors and other endocrine therapies.