Proteasome-mediated proteolysis of estrogen receptor: A novel component in autologous down-regulation
Proteasome-mediated proteolysis of estrogen receptor: A novel component in autologous down-regulation
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DOI：
10.1210/me.13.9.1522
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发表时间：
1999-09-01
影响因子：
--
通讯作者：
Solodin, N
中科院分区：
文献类型：
--
作者：
Alarid, ET;Bakopoulos, N;Solodin, N
雌激素受体（ER）浓度的调节是限制靶细胞雌激素反应性的关键因素，但雌激素作用的主要部位垂体前叶催乳细胞中ER浓度的调节机制尚未确定。在本研究中，我们使用催乳细胞系PR 1来探索雌激素对ER蛋白的调节，雌激素处理导致ER稳态蛋白水平降低约60%。令人惊讶的是，雌激素治疗1小时内ER蛋白的下降是明显的，发生在蛋白质合成和转录的情况下。脉冲追踪分析进一步证实了雌激素对ER蛋白的直接调节作用，表明雌激素可使ER蛋白的半衰期从3 h以上缩短至1h。蛋白酶体蛋白酶的肽醛抑制剂预处理可阻止雌激素诱导的ER蛋白降解，而钙蛋白酶和溶酶体蛋白酶的抑制剂则无效。蛋白酶体活性的抑制将ER蛋白维持在与未用雌激素刺激的对照细胞相当的水平，但使雌激素结合活性增加1.75倍。蛋白酶体对ER的蛋白水解调节不限于垂体催乳细胞，而且在MCF-7乳腺癌细胞中也是有效的，这些研究描述了雌激素的一种非基因组作用，涉及核ER：通过蛋白酶体介导的途径快速蛋白水解ER蛋白。
Regulation of estrogen receptor (ER) concentration is a key component in limiting estrogen responsiveness in target cells, Yet the mechanisms governing ER concentration in the lactotrope cells of the anterior pituitary, a major site of estrogen action, are undetermined. In this study, we used a lactotrope cell line, PR1, to explore regulation of ER protein by estrogen, Estrogen treatment resulted in an approximate 60% decrease in ER steady state protein levels. Suprisingly, the decline in ER protein was apparent within 1 h of estrogen treatment and occurred in the absence of protein synthesis and transcription. Direct regulation of ER protein was further confirmed by pulse chase analysis, which showed that ER protein half-life was shortened from greater than 3 h to 1 h in the presence of estrogen, The estrogen-induced degradation of ER protein could be prevented by pretreatment with peptide aldehyde inhibitors of proteasome protease whereas inhibitors of calpain and lysosomal proteases were ineffective, Inhibition of proteasome activity maintained ER protein at a level equivalent to control cells not stimulated with estrogen but increased estrogen-binding activity by 1.75-fold, Proteolytic regulation of ER by the proteasome is not limited to pituitary lactotrope cells but is also operational in MCF-7 breast cancer cells, suggesting that this may be a common regulatory pathway used by estrogen, These studies describe a nongenomic action of estrogen that involves nuclear ER: rapid proteolysis of ER protein via a proteasome-mediated pathway.