Altered target gene regulation controlled by estrogen receptor-α concentration
Altered target gene regulation controlled by estrogen receptor-α concentration
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DOI：
10.1210/me.2005-0288
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发表时间：
2006-02-01
影响因子：
--
通讯作者：
Alarid, ET
中科院分区：
文献类型：
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作者：
Fowler, AM;Solodin, NM;Alarid, ET
雌激素受体-α (ER α) 是一种转录激活剂，其浓度受到细胞环境的严格调节。在绝经后妇女的乳腺肿瘤中，受体浓度升高可能与负面的临床结果相关，但人们对如此高的水平如何影响 ER α 功能仍知之甚少。我们之前证明，乳腺癌细胞中高核浓度的 ER α 绕过了对配体的需求，足以激活转录并加速增殖。在这里，我们扩展了这些研究，并询问转录靶点和激活机制与雌激素刺激的 ER α 是否相似或不同。我们发现，在升高的水平下，ER α 会激活，但不能抑制已知的雌激素反应基因。此外，激活基因组被扩展为包括子宫限制性靶基因、补体成分3。在这些条件下ERα的激活机制取决于激活函数1和配体结合结构域近端区域中的残基。天冬氨酸 351 和亮氨酸 372 的突变可以抑制高浓度下获得的 ER α 转录活性，并将浓度诱导的 ER α 功能与雌激素诱导的功能区分开来。此外，我们证明，在高水平下，ER α 可以刺激转录，而无需募集类固醇受体辅激活因子 3，也不会受到包含 LxxLL 基序的 Gal4-受体相互作用域盒融合蛋白的干扰，进一步将这种调节模式与已知的激活机制区分开来。这些结果共同证明乳腺癌细胞中受体的浓度可以通过非典型激活机制影响靶基因表达模式。
Estrogen receptor-alpha (ER alpha) is a transcriptional activator whose concentration is tightly regulated by the cellular environment. In breast tumors of postmenopausal women, elevated receptor concentrations can be associated with negative clinical outcomes, yet it remains poorly understood how such high levels impact ER alpha function. We previously demonstrated that high nuclear concentrations of ER alpha in breast cancer cells bypass the requirement for ligand and are sufficient to activate transcription and accelerate proliferation. Here, we extended those studies and asked whether the transcriptional targets and activation mechanism are similar or different from that of estrogen-stimulated ER alpha. We found that at elevated levels, ER alpha activated, but could not repress, known estrogen-responsivegenes. Moreover, the set of activated genes was expanded to include the uterine-restricted target gene, complement component 3. The activation mechanism of ER alpha under these conditions depends both on activation function-1 and residues in the proximal region of the ligand-binding domain. Mutations of aspartate 351 and leucine 372 can inhibit ER alpha transcriptional activity gained at high concentrations and discriminate concentration-inducible ER alpha function from that induced by estrogen. Moreover, we demonstrate that at high levels, ER alpha stimulates transcription without recruiting steroid receptor coactivator-3 and without interference by a Gal4-receptor interaction domain box fusion protein containing LxxLL motifs, further distinguishing this mode of regulation from known activation mechanisms. Together these results demonstrate that the concentration of receptor in breast cancer cells can influence the pattern of target gene expression through a noncanonical activation mechanism.