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首页> 外文期刊>Cellular Signalling >Methylosome protein 50 promotes androgen- and estrogen-independent tumorigenesis
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Methylosome protein 50 promotes androgen- and estrogen-independent tumorigenesis

机译：甲基脂质体蛋白50促进不依赖雄激素和雌激素的肿瘤发生

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摘要

Methylosome protein 50 (MEP50) is a component of methylosome where MEP50 binds protein substrates and activates the oncogenic protein arginine methyl transferase 5 (PRMT5). MEP50 is also a coactivator for androgen receptor (AR) and estrogen receptor (ER), and transforms cells in the presence of androgen or estrogen. To extend the understanding of howMEP50 transforms cells, we investigated whetherMEP50 could transformcells independent of AR and ER, and clarifiedwhether PRMT5 could contribute to the MEP50-caused tumor formation.Microarray and Western blot analyses revealed the association of MEP50 with many human cancers including lung cancer. Knockdown of MEP50 retarded cell growth and migration in selected lung cancer cell lines, which expressed very lowlevel of AR and ER and were insensitive to inhibitors of AR and ER. Moreover, overexpression of Myc-MEP50 enhanced cell transforming activities of 293T cells which are known lack of expression of AR and ER.Mechanistic analyses showed that MEP50 controlled G2 progression, upregulated cyclin-dependent kinase 1(CDK1)/cyclin B1, and activated the survival cascade Phosphoinositide 3-kinase (PI3K)/AKT. MEP50 promoted cellmigration, and activated the cellmigration pathways such as Ras-related C3 botulinumtoxin substrate 1 (Rac1)/vasodilator-stimulated phosphoprotein (VASP), and forkhead box protein A2 (FOXA2)/slug/cadherin cascades. Further analyses revealed that MEP50 activated the survival factor PI3K through PRMT5-catalyzed dimethylation of PI3K. Collectively, it is concluded that MEP50 can transform cells independent of AR and ER, and PRMT5 has partial contribution to that process.
机译：甲基脂质体蛋白50（MEP50）是甲基脂质体的成分，其中MEP50结合蛋白底物并激活致癌蛋白精氨酸甲基转移酶5（PRMT5）。 MEP50还是雄激素受体（AR）和雌激素受体（ER）的共激活因子，在雄激素或雌激素存在下转化细胞。为了扩展对MEP50转化细胞的了解，我们研究了MEP50是否可以转化不依赖于AR和ER的细胞，并阐明了PRMT5是否有助于MEP50引起的肿瘤形成。微阵列和Western blot分析揭示了MEP50与许多人类癌症（包括肺癌）的关联。敲低MEP50抑制了某些肺癌细胞株的细胞生长和迁移，这些肺癌细胞中AR和ER的表达水平很低，并且对AR和ER的抑制剂不敏感。此外，Myc-MEP50的过表达增强了293T细胞的细胞转化活性，而293T细胞却缺乏AR和ER的表达。机理分析表明，MEP50控制G2的进程，上调细胞周期蛋白依赖性激酶1（CDK1）/细胞周期蛋白B1并激活细胞生存级联磷酸肌醇3-激酶（PI3K）/ AKT。 MEP50促进细胞迁移，并激活细胞迁移途径，例如Ras相关的C3肉毒毒素底物1（Rac1）/血管扩张剂刺激的磷蛋白（VASP）和叉头盒蛋白A2（FOXA2）/团/钙粘蛋白级联反应。进一步的分析表明，MEP50通过PRMT5催化的PI3K的二甲基化激活了生存因子PI3K。总体而言，得出的结论是MEP50可以转化独立于AR和ER的细胞，而PRMT5对该过程具有部分贡献。

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