Potential role of a novel transcriptional coactivator PELP1 in histone H1 displacement in cancer cells
Potential role of a novel transcriptional coactivator PELP1 in histone H1 displacement in cancer cells
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DOI：
10.1158/0008-5472.can-04-1786
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发表时间：
2004-09-15
期刊：
影响因子：
11.2
通讯作者：
Vadlamudi, RK
中科院分区：
文献类型：
--
作者：
Nair, SS;Mishra, SK;Vadlamudi, RK
雌激素受体在乳腺癌进展中起重要作用。富含脯氨酸、谷氨酸和亮氨酸的蛋白I（Proline-，glutamic-，and leucine-rich protein I，PELP 1）又称雌激素受体非基因组活性调节因子（modulator of nongenomic activity of estrogen receptor，MNAR），是一种新型的雌激素受体共激活因子，可调节雌激素受体的反式激活功能。PELP 1调节雌激素受体基因组功能的机制尚不清楚。在这里，使用生化和扫描共聚焦显微镜分析，我们已经证明了PELP 1的核定位和功能的影响。亚核分级显示PELP 1与染色质和核基质组分相关。配体刺激促进了PELP 1对17 β-雌二醇应答启动子的募集，其与乙酰化H3的共定位，并增加了PELP 1相关的组蛋白乙酰转移酶的酶活性。远Western分析显示，PELPI与组蛋白1和3相互作用，更倾向于组蛋白1。使用缺失分析，我们已经确定PELPI COOH-末端区域作为组蛋白1结合位点。缺乏组蛋白1结合结构域的PELP 1突变体作为显性负调控因子，阻断雌激素受体α介导的转录。染色质免疫沉淀分析显示PELP 1与启动子的循环关联和解离，组蛋白1和PELP 1的募集发生在相反的阶段。PELPI过表达增加了含雌激素反应元件核小体的微球菌核酸酶敏感性。我们的研究结果提供了关于PELPI转录调控的新见解，并表明PELP 1通过置换癌细胞中的组蛋白1参与染色质重塑活动。
The estrogen receptor plays an important role in breast cancer progression. Proline-, glutamic acid-, and leucine-rich protein I (PELP1), also called modulator of nongenomic activity of estrogen receptor (MNAR), a novel coactivator of estrogen receptor, modulates estrogen receptor transactivation functions. The mechanisms by which PELP1 modulates estrogen receptor genomic functions is not known. Here, using biochemical and scanning confocal microscopic analysis, we have demonstrated nuclear localization and functional implications of PELP1. Subnuclear fractionation showed PELP1 association with chromatin and nuclear matrix fractions. Ligand stimulation promoted recruitment of PELP1 to 17beta-estradiol responsive promoters, its colocalization with acetylated H3, and increased PELP1-associated histone acetyltransferase enzymatic activity. Far Western analysis revealed that PELPI interacts with histone 1 and 3, with more preference toward histone 1. Using deletion analysis, we have identified the PELPI COOH-terminal region as the histone 1 binding site. The PELP1 mutant lacking histone 1-binding domain acts as a dominantnegative and blocks estrogen receptor alpha-mediated transcription. Chromatin immunoprecipitation analysis showed a cyclic association and dissociation of PELP1 with the promoter, with recruitment of histone 1 and PELP1 occurring in opposite phases. PELPI overexpression increased the micrococcal nuclease sensitivity of estrogen response element-containing nucleosomes. Our results provide novel insights about the transcription regulation of PELPI and suggest that PELP1 participates in chromatin remodeling activity via displacement of histone 1 in cancer cells.