Involvement of suppressor for Gal 1 in the ubiquitin/proteasome-mediated degradation of estrogen receptors
Involvement of suppressor for Gal 1 in the ubiquitin/proteasome-mediated degradation of estrogen receptors
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DOI：
10.1074/jbc.m312762200
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发表时间：
2004-03-26
影响因子：
4.8
通讯作者：
Hiramatsu, Y
中科院分区：
文献类型：
--
作者：
Masuyama, H;Hiramatsu, Y
蛋白酶体介导的途径涉及几种核受体的降解。以前，我们证明，抑制Gal 1（SUG 1）和核受体，维生素D受体，或维生素X受体之间的相互作用参与蛋白酶体介导的降解。在我们最近的实验中，我们研究了SUG 1在蛋白酶体介导的雌激素受体（ER）α和β降解中的潜在作用。两种ER均以配体依赖性方式与SUG 1相互作用。在功能上，SUG 1的过表达在配体存在下抑制ER α和ER β介导的转录。瞬时表达研究表明，野生型SUG 1的过度表达产生的蛋白水解片段的ER和这些产品被阻断的蛋白酶体抑制剂。SUG 1的过表达也增强了配体存在下两种ER的泛素化蛋白的形成。另一方面，激活ER介导的转录的双酚A（BSA）并没有增强ER β和SUG 1之间的相互作用。此外，在BSA存在下，ER β的降解比在雌二醇或邻苯二甲酸酯（另一种内分泌干扰化学品）存在下慢得多。此外，BSA对ER β的蛋白水解片段的形成没有影响，并且对ER β的泛素化也没有任何影响。这些发现表明，泛素/蛋白酶体介导的降解两个ER蛋白可能涉及SUG 1与两个ER的相互作用。与雌二醇相比，BSA能显著抑制ER β的泛素化和降解，提示BSA可能通过抑制ER β降解而影响ER β介导的靶基因转录。
The proteasome-mediated pathway involves the degradation of several nuclear receptors. Previously we demonstrated that the interaction between the suppressor for Gal 1 (SUG1) and nuclear receptors, the vitamin D receptor, or the pregnane X receptor was involved in proteasome-mediated degradation. In our recent experiments, we examined the potential role of SUG1 in the proteasome-mediated degradation of estrogen receptors (ER)alpha and - beta. Both ERs interacted with SUG1 in a ligand-dependent manner. Functionally, the overexpression of SUG1 inhibited both ERalpha- and ERbeta-mediated transcription in the presence of ligands. Transient expression studies demonstrated that the overexpression of wildtype SUG1 generated proteolytic fragments of both ERs and that these products were blocked by a proteasome inhibitor. The overexpression of SUG1 also enhanced the formation of ubiquitinated proteins of both ERs in the presence of ligand. On the other hand, bisphenol A (BSA), which activated ER-mediated transcription, did not enhance the interaction between ERbeta and SUG1. Furthermore, the degradation of ERbeta was much slower in the presence of BSA than in the presence of estradiol or phthalate, which is another endocrine-disrupting chemical. Also, BSA had no effect on the formation of proteolytic fragments of ERbeta, and neither did it have any effect on the ubiquitination of ERbeta. These findings indicate that the ubiquitin/proteasome-mediated degradation of both ER proteins may involve the interaction of SUG1 with both ERs. Moreover, BSA strongly blocked the ubiquitination and degradation of ERbeta compared with estradiol, suggesting that BSA may affect the ERbeta-mediated transcription of target genes by inhibiting ERbeta degradation.