The 26S proteasome is required for estrogen receptor-α and coactivator turnover and for efficient estrogen receptor-α transactivation
The 26S proteasome is required for estrogen receptor-α and coactivator turnover and for efficient estrogen receptor-α transactivation
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DOI：
10.1016/s1097-2765(00)80259-2
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发表时间：
2000-06-01
期刊：
影响因子：
16
通讯作者：
O'Malley, BW
中科院分区：
文献类型：
--
作者：
Lonard, DM;Nawaz, Z;O'Malley, BW
雌激素受体α (ER α)在其同源配体雌二醇（E2）存在时，通过泛素蛋白酶体途径下调。在这里，我们证明了泛素蛋白酶体的功能是ER α作为转录激活剂所必需的。删除ER α的最后61个氨基酸，包括形成螺旋12的残基，会消除配体介导的受体下调，就像配体结合区域的点突变会损害辅激活剂的结合一样。此外，共激活因子也会被26S蛋白酶体降解，但其固有的转录活性不受影响。这些数据证明，蛋白质与内质网α辅激活因子结合表面的相互作用对配体介导的受体下调很重要，并表明受体和辅激活因子的转换有助于内质网α转录活性。
Estrogen receptor-alpha (ER alpha) is downregulated in the presence of its cognate ligand, estradiol (E2), through the ubiquitin proteasome pathway. Here, we show that ubiquitin proteasome function is required for ER alpha to serve as a transcriptional activator. Deletion of the last 61 amino acids of ER alpha, including residues that form helix 12, abolishes ligand-mediated downregulation of the receptor as do point mutations in the ligand binding domain that impair coactivator binding. In addition, coactivators also are subject to degradation by the 26S proteasome, but their intrinsic transcriptional activity is not affected. These data provide evidence that protein interactions with ER alpha coactivator binding surfaces are important for ligand-mediated receptor downregulation and suggest that receptor and coactivator turnover contributes to ER alpha transcriptional activity.