Proteasome-dependent degradation of the human estrogen receptor
Proteasome-dependent degradation of the human estrogen receptor
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DOI：
10.1073/pnas.96.5.1858
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发表时间：
1999-03-02
影响因子：
11.1
通讯作者：
O'Malley, BW
中科院分区：
文献类型：
--
作者：
Nawaz, Z;Lonard, DM;O'Malley, BW
在真核细胞中，遍在蛋白-蛋白酶体途径是靶向降解半衰期短的蛋白质的主要机制。泛素与靶蛋白的赖氨酸残基的共价连接是蛋白酶体（一种大型多亚基蛋白酶）识别和快速降解的信号。在这份报告中，我们证明了人类雌激素受体（ER）蛋白在哺乳动物细胞中以雌二醇依赖的方式迅速降解。用蛋白酶体抑制剂MG 132处理哺乳动物细胞抑制蛋白酶体的活性并阻断ER降解，表明ER蛋白通过泛素-蛋白酶体途径被翻转。此外，我们发现，在体外ER的降解依赖于泛素激活E1酶（乌巴）和泛素结合E2酶（UBC），和蛋白酶体抑制剂MG 132和lactacystin阻断ER蛋白的体外降解。此外，乌巴/UBC和蛋白酶体抑制剂促进ER的较高分子量形式的积累。体外促进ER降解的乌巴和UBC对人孕酮受体和人甲状腺激素受体β蛋白无明显影响。
In eukaryotic cells, the ubiquitin-proteasome pathway is the major mechanism for the targeted degradation of proteins with short half-lives. The covalent attachment of ubiquitin to lysine residues of targeted proteins is a signal for the recognition and rapid degradation by the proteasome, a large multi-subunit protease. In this report, we demonstrate that the human estrogen receptor (ER) protein is rapidly degraded in mammalian cells in an estradiol-dependent manner. The treatment of mammalian cells with the proteasome inhibitor MG132 inhibits activity of the proteasome and blocks ER degradation, suggesting that ER protein is turned over through the ubiquitin-proteasome pathway. In addition, we show that in vitro ER degradation depends on ubiquitin-activating E1 enzyme (UBA) and ubiquitin-conjugating E2 enzymes (UBCs), and the proteasome inhibitors MG132 and lactacystin block ER protein degradation in vitro. Furthermore, the UBA/UBCs and proteasome inhibitors promote the accumulation of higher molecular weight forms of ER. The UBA and UBCs, which promote ER degradation in vitro, have no significant effect on human progesterone receptor and human thyroid hormone receptor beta proteins.