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首页> 外文期刊>Molecular and Cellular Biology >Transcriptional Regulation of the MDR1 Gene by Histone Acetyltransferase and Deacetylase Is Mediated by NF-Y
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Transcriptional Regulation of the MDR1 Gene by Histone Acetyltransferase and Deacetylase Is Mediated by NF-Y

机译：NF-Y介导组蛋白乙酰转移酶和脱乙酰基酶对MDR1基因的转录调控

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Recent studies have shown that the histone-modifying enzymes histone acetyltransferase (HAT) and histone deacetylase (HDAC) are involved in transcriptional activation and repression, respectively. However, little is known about the endogenous genes that are regulated by these enzymes or how specificity is achieved. In the present report, we demonstrate that HAT and HDAC activities modulate transcription of the P-glycoprotein-encoding gene, MDR1. Incubation of human colon carcinoma SW620 cells in 100-ng/ml trichostatin A (TSA), a specific HDAC inhibitor, increased the steady-state level ofMDR1 mRNA 20-fold. Furthermore, TSA treatment of cells transfected with a wild-type MDR1 promoter/luciferase construct resulted in a 10- to 15-fold induction of promoter activity. Deletion and point mutation analysis determined that an inverted CCAAT box was essential for this activation. Consistent with this observation, overexpression of p300/CREB binding protein-associated factor (P/CAF), a transcriptional coactivator with intrinsic HAT activity, activated the wild-type MDR1 promoter but not a promoter containing a mutation in the CCAAT box; deletion of the P/CAF HAT domain abolished activation. Gel shift and supershift analyses identified NF-Y as the CCAAT-box binding protein in these cells, and cotransfection of a dominant negative NF-Y expression vector decreased the activation of the MDR1promoter by TSA. Moreover, NF-YA and P/CAF were shown to interact in vitro. This is the first report of a natural promoter that is modulated by HAT and HDAC activities in which the transcription factor mediating this regulation has been identified.
机译：最近的研究表明，组蛋白修饰酶组蛋白乙酰转移酶（HAT）和组蛋白脱乙酰基酶（HDAC）分别参与转录激活和抑制。然而，对于由这些酶调节的内源基因或如何实现特异性知之甚少。在本报告中，我们证明HAT和HDAC活性可调节P糖蛋白编码基因 MDR1 的转录。将人类结肠癌SW620细胞与一种特异的HDAC抑制剂100ng / ml曲古抑菌素A（TSA）孵育，可使 MDR1 mRNA的稳态水平提高20倍。此外，TSA处理野生型 MDR1 启动子/荧光素酶构建体转染的细胞可导致启动子活性诱导10到15倍。删除和点突变分析确定倒置的CCAAT盒对于此激活至关重要。与该观察结果一致，具有固有HAT活性的转录共激活因子p300 / CREB结合蛋白相关因子（P / CAF）的过表达激活了野生型 MDR1 启动子，但未激活包含突变的启动子在CCAAT框中; P / CAF HAT域的删除取消了激活。凝胶移位和超移位分析确定了NF-Y是这些细胞中的CCAAT-box结合蛋白，并且显性阴性NF-Y表达载体的共转染减少了TSA对 MDR1 启动子的激活。而且，NF-YA和P / CAF显示出在体外相互作用。这是由HAT和HDAC活性调节的天然启动子的首次报道，其中已确定了介导该调控的转录因子。

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