Xenoestrogens Regulate the Activity of Arginine Methyltransferases
Xenoestrogens Regulate the Activity of Arginine Methyltransferases
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DOI：
10.1002/cbic.201000522
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发表时间：
2011-01-24
期刊：
影响因子：
3.2
通讯作者：
Bedford, Mark T.
中科院分区：
文献类型：
--
作者：
Cheng, Donghang;Bedford, Mark T.
精氨酸甲基化是一种常见的翻译后修饰，与转录调控密切相关。精氨酸甲基转移酶（PRMTs）作为雌激素和雄激素受体的转录辅激活因子首次被报道。抑制这些酶的化合物将为我们提供解剖这些酶在细胞中的作用的有价值的工具，并且还可能具有治疗应用。为了鉴定PRMT的这种抑制剂，我们先前已经使用小分子文库进行了高通量筛选。这些化合物被命名为精氨酸甲基转移酶抑制剂（AMI）。这些抑制剂中的大多数是多酚，特别是一种（AMI-18）与一组已知的异种雌激素共享额外的功能。因此，我们测试了一组异种雌激素，发现其中一些具有体外抑制PRMT活性的能力。这些抑制剂主要靶向CARM 1，包括甘草查尔酮A、酮、4-羟基苯甲酸苄酯和他莫昔芬。我们开发了一种基于细胞的报告系统的CARM 1活性，并表明，他莫昔芬（IC 50 = 30 μ m）抑制这种PRMT。这些化合物调节转录辅激活因子活性的能力可能是异种雌激素的一种未被认识到的作用机制，也可能解释高剂量他莫昔芬治疗雌激素受体阴性癌症的疗效。
Arginine methylation is a common post-translational modification that has been strongly implicated in transcriptional regulation. The arginine methyltransferases (PRMTs) were first reported as transcriptional coactivators for the estrogen and androgen receptors. Compounds that inhibit these enzymes will provide us with valuable tools for dissecting the roles of these enzymes in cells, and will possibly also have therapeutic applications. In order to identify such inhibitors of the PRMTs, we have previously performed a high-throughput screen using a small molecule library. These compounds were named arginine methyltransferase inhibitors (AMIs). The majority of these inhibitors were polyphenols, and one in particular (AMI-18) shared additional features with a group of known xenoestrogens. We, thus, tested a panel of xenoestrogens and found that a number of them possess the ability to inhibit PRMT activity, in vitro. These inhibitors primarily target CARM1, and include licochalcone A, kepone, benzyl 4-hydroxybenzoate, and tamoxifen. We developed a cell-based reporter system for CARM1 activity, and showed that tamoxifen (IC50 = 30 mu m) inhibits this PRMT. The ability of these compounds to regulate the activity of transcriptional coactivators may be an unappreciated mechanism of action for xenoestrogens, and might also explain the efficacy of high-dose tamoxifen treatment on estrogen receptor negative cancers.