Estradiol repression of tumor necrosis factor-α transcription requires estrogen receptor activation function-2 and is enhanced by coactivators
Estradiol repression of tumor necrosis factor-α transcription requires estrogen receptor activation function-2 and is enhanced by coactivators
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DOI：
10.1073/pnas.96.26.15161
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发表时间：
1999-12-21
影响因子：
11.1
通讯作者：
Leitman, DC
中科院分区：
文献类型：
--
作者：
An, JP;Ribeiro, RCJ;Leitman, DC
肿瘤坏死因子-α (TNF-α) 启动子用于探索雌二醇 (E-2) 依赖性基因转录抑制的分子机制。 E-2抑制基础活性并消除TNF-α启动子的TNF-α激活。 E-2 抑制元件被定位到 TNF-α 启动子的 -125 至 -82 区域，称为 TNF 响应元件 (TNF-RE)。TNF-RE 中的 AP-1 样位点对于抑制活性至关重要。雌激素受体 (ER) β 在抑制 -1044 TNF-α 启动子和单纯疱疹病毒胸苷激酶启动子上游的 TNF-RE 方面比 ER α 更有效，但在通过雌激素反应元件激活转录方面较弱。配体结合域中的激活功能 2 (AF-2) 表面是抑制所必需的，因为抗雌激素和 AF-2 突变会损害抑制。 AF-2 表面的抑制作用可能是由于其招募 p160 共激活因子或相关共调节因子的能力，因为过表达共激活因子糖皮质激素受体相互作用蛋白 1 会增强抑制作用，而无法与 AF-2 表面相互作用的糖皮质激素受体相互作用蛋白 1 突变体则无效。此外，受体相互作用蛋白 140 可能通过与 AF-2 表面相互作用并阻断内源性共激活因子的结合来防止 ERP 的抑制。这些研究表明，E-2 介导的抑制需要 AF-2 表面以及共激活因子或其他共调节蛋白的参与。
The tumor necrosis factor-alpha (TNF-alpha) promoter was used to explore the molecular mechanisms of estradiol (E-2)-dependent repression of gene transcription. E-2 inhibited basal activity and abolished TNF-alpha activation of the TNF-alpha promoter. The E-2-inhibitory element was mapped to the -125 to -82 region of the TNF-alpha promoter, known as the TNF-responsive element (TNF-RE), An AP-1-like site in the TNF-RE is essential for repression activity. Estrogen receptor (ER) beta is more potent than ER alpha at repressing the -1044 TNF-alpha promoter and the TNF-RE upstream of the herpes simplex virus thymidine kinase promoter, but weaker at activating transcription through an estrogen response element. The activation function-2 (AF-2) surface in the ligand-binding domain is required for repression, because anti-estrogens and AF-2 mutations impair repression. The requirement of the AF-2 surface for repression is probably due to its capacity to recruit p160 coactivators or related coregulators, because overexpressing the coactivator glucocorticoid receptor interacting protein-1 enhances repression, whereas a glucocorticoid receptor interacting protein-1 mutant unable to interact with the AF-2 surface is ineffective. Furthermore, receptor interacting protein 140 prevents repression by ERP, probably by interacting with the AF-2 surface and blocking the binding of endogenous coactivators, These studies demonstrate that E-2-mediated repression requires the AF-2 surface and the participation of coactivators or other coregulatory proteins.