Estrogen receptor activation at serine 305 is sufficient to upregulate cyclin D1 in breast cancer cells
Estrogen receptor activation at serine 305 is sufficient to upregulate cyclin D1 in breast cancer cells
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DOI：
10.1016/j.febslet.2004.04.071
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发表时间：
2004-06-04
期刊：
影响因子：
3.5
通讯作者：
Kumar, R
中科院分区：
文献类型：
--
作者：
Balasenthil, S;Barnes, CJ;Kumar, R
最近的研究表明，p21激活激酶1（Pak 1）磷酸化雌激素受体（ER）的Ser 305，并促进其反式激活功能。在这里，我们试图研究是否在ER丝氨酸305取代谷氨酸（ER-S305 E），这模拟磷酸化状态，会影响ER靶基因的状态。为了探索这种可能性，我们在ER阴性的MDA-MB-231细胞中产生了过表达ER-S305 E的克隆，并使用基因阵列分析了ER调节基因的状态。结果表明，ER-S305 E的表达足以上调少数但不是所有ER调节基因的表达，即，细胞周期蛋白D1和锌指蛋白147（雌激素响应指蛋白），而在阵列上的其余基因的表达没有显着变化。此外，我们发现，与表达WT-ER或pcDNA的MDA-MB-231细胞中的细胞周期蛋白D1水平相比，表达ER-S305 E的MDA-MB-231细胞中的细胞周期蛋白D1蛋白的表达增加以及核积累。此外，ER-S305 E，而不是ER-S305突变为丙氨酸，增强细胞周期蛋白D1启动子活性。这些发现表明，ER在S305的激活足以上调细胞周期蛋白D1的表达，细胞周期蛋白D1是一种ER调节的基因，与乳腺癌的进展有关。Pak 1或其上游调控因子对ER的磷酸化可以以配体非依赖性的方式上调ER靶基因亚组的表达，因此，可能有助于乳腺癌细胞中激素非依赖性的发展。(C)2004年欧洲生物化学学会联合会。Elsevier B. V.出版，保留所有权利。
Recent studies have shown that p21-activated kinase 1 (Pak1) phosphorylates estrogen receptor- (ER) at Ser 305 and also promotes its transactivation function. Here, We sought to investigate whether substitution of serine 305 in ER with glutamic acid (ER-S305E), which mimics the phosphorylation state, would influence the status of ER-target genes. To explore this possibility, we generated clones overexpressing ER-S305E in ER-negative MDA-MB-231 cells and analyzed the status of ER-regulated genes using a gene array. Results indicated that the expression of ER-S305E is sufficient to upregulate the expression of a few but not all ER-regulated genes, i.e., cyclin D1 and zinc finger protein 147 (estrogen-responsive finger protein), while there was no significant change in the expression of remaining genes on the array. In addition, we found an increased expression as well as nuclear accumulation of cyclin D1 protein in MDA-MB-231 cells expressing ER-S305E as compared to the level of cyclin D1 in MDA-MB-231 cells expressing WT-ER or pcDNA. Furthermore, ER-S305E, but not mutation of ER-S305 to alanine, enhanced the cyclin D1 promoter activity. These findings suggest that ER activation at S305 is sufficient to upregulate the expression of cyclin D1, an ER-regulated gene that is implicated in the progression of breast cancer. Phosphorylation of ER by Pak1 or its upstream regulators could upregulate the expression of a subset of ER-target genes in a ligand-independent manner and hence, might contribute toward the development of hormone independence in breast cancer cells. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.