Yin Yang 1 enhances cyclooxygenase-2 gene expression in macrophages
Yin Yang 1 enhances cyclooxygenase-2 gene expression in macrophages
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DOI：
10.1152/ajplung.00474.2006
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发表时间：
2007-05-01
影响因子：
4.9
通讯作者：
Christman, John W.
中科院分区：
文献类型：
--
作者：
Joo, Myungsoo;Wright, Jeffrey G.;Christman, John W.
环氧合酶-2 (COX-2) 的表达与炎症和各种癌症（包括肺癌）的发病机制有关。 Yin Yang 1 (YY1) 是一种锌指转录因子，其转录活性与组蛋白乙酰转移酶和脱乙酰酶相互作用，并且还参与炎症和肿瘤发生。我们研究了 YY1 是否调节 COX-2 表达。我们定位了一个可能的 YY1 结合位点，靠近 COX-2 启动子的转录起始位点。电泳迁移率变动分析表明，YY1 在体外与假定的 YY1 位点结合。为了显示生物学相关性，我们进行了染色质免疫沉淀测定，结果表明脂多糖 (LPS) 处理诱导 YY1 与内源 COX-2 启动子中的同源位点结合。在用 LPS 或活铜绿假单胞菌处理的巨噬细胞中 YY1 的过度表达增加了 COX-2 转录活性。此外，YY1 增强了 LPS 处理引起的 COX-2 蛋白表达和前列腺素 D2 产生。从机制上讲，我们观察到 LPS 处理导致 YY1 和 p300（一种组蛋白乙酰转移酶）之间的相互作用中断，但不影响 YY1 和组蛋白脱乙酰酶 1/2 之间的相互作用。这些数据表明，响应 LPS，YY1 从 p300 解离并与 COX-2 启动子结合，有助于炎症环境中 COX-2 的表达。
Expression of cyclooxygenase-2 (COX-2) is associated with the pathogenesis of inflammation and various cancers, including lung cancer. Yin Yang 1 (YY1) is a zinc-finger transcription factor that interacts with histone acetyltransferases and deacetylases for its transcriptional activity and also is involved in inflammation and tumorigenesis. We investigated whether YY1 regulates COX-2 expression. We located a possible YY1 binding site proximal to the transcription initiation site of the COX-2 promoter. Electrophoretic mobility shift assays show that YY1 bound to the putative YY1 site in vitro. To show biological relevance, we performed chromatin immunoprecipitation assays showing that lipopolysaccharide (LPS) treatment induced YY1 binding to the cognate site in the endogenous COX-2 promoter. Overexpression of YY1 in macrophages treated with either LPS or live Pseudomonas aeruginosa increased COX-2 transcriptional activity. Furthermore, YY1 enhanced COX-2 protein expression and prostaglandin D2 production elicited by LPS treatment. Mechanistically, we observed that LPS treatment resulted in disruption of an interaction between YY1 and p300, a histone acetyltransferase, but did not affect the interaction between YY1 and histone deacetylase 1/2. These data suggest that in response to LPS, YY1 dissociates from p300 and binds to the COX-2 promoter, contributing to COX-2 expression in an inflammatory milieu.