The role of calcium in the activation of estrogen receptor-alpha.
The role of calcium in the activation of estrogen receptor-alpha.
复制标题
DOI：
10.1158/0008-5472.can-10-1899
复制
发表时间：
2011-03-01
期刊：
影响因子：
11.2
通讯作者：
Martin MB
中科院分区：
文献类型：
--
作者：
Divekar SD;Storchan GB;Sperle K;Veselik DJ;Johnson E;Dakshanamurthy S;Lajiminmuhip YN;Nakles RE;Huang L;Martin MB
环境雌激素类似物，包括可以激活雌激素受体-α(ER-α)的金属雌激素，可能与乳腺癌的风险有关。然而，这些分子模拟物激活雌激素受体-α的潜在机制通常知之甚少。出于对这一重要问题的关注，我们研究了细胞内钙是否可能介导了激活ERα的信号通路和ERα的配体结合域之间的串扰。用表皮生长因子、三磷酸腺苷、细胞外钙或咖啡因处理MCF-7细胞以增加细胞内钙离子，可触发ERα快速募集到雌激素反应启动子，并刺激雌激素反应基因的表达，包括pS2、补体C3和孕激素受体。诱导被抗雌激素阻断，但也被细胞内钙离子的螯合所阻断。细胞外钙处理也通过ER依赖机制促进MCF-7细胞的生长。我们发现，表皮生长因子和细胞外钙激活ERα的C末端，该激活可被抗雌激素阻断。机制研究发现，ERα配体结合域的溶剂可及表面上的四个潜在位点对受体的钙激活具有重要作用。综上所述，我们的结果表明，钙介导了ERα激活信号通路和ERα配体结合域之间的串扰，为某些环境金属雌激素激活受体的能力提供了潜在的解释。
Environmental estrogen mimics, including metalloestrogens that can activate estrogen receptor-alpha (ERα), may contribute to breast cancer risk. However, the underlying mechanisms through which these molecular mimics activate the estrogen receptor-alpha are generally, poorly understood. With concern to this important question, we investigated whether intracellular calcium may mediate the crosstalk between signaling pathways that activate ERα and the ligand binding domain of ERα. MCF-7 cells treated with EGF, ATP, extracellular calcium, or caffeine to increase intracellular calcium triggered a rapid recruitment of ERα to estrogen responsive promoters and stimulated expression of estrogen responsive genes including pS2, complement C3, and progesterone receptor. Induction was blocked by an antiestrogen but also by the chelation of intracellular calcium. Treatment with extracellular calcium also increased the growth of MCF-7 cells through an ER dependent mechanism. We found that EGF and extracellular calcium activated the C-terminus of ERα and the activation was blocked by the antiestrogen. Mechanistic investigations identified four potential sites on the solvent accessible surface of the ERα ligand binding domain as important for calcium activation of the receptor. Taken together, our results suggest that calcium mediates the crosstalk between ERα–activating signaling pathways and the ligand binding domain of ERα providing a potential explanation for the ability of certain environmental metalloestrogens to activate the receptor.