Corticosteroids induce cyclooxygenase 1 expression in cardiomyocytes: role of glucocorticoid receptor and Sp3 transcription factor.
Corticosteroids induce cyclooxygenase 1 expression in cardiomyocytes: role of glucocorticoid receptor and Sp3 transcription factor.
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DOI：
10.1210/me.2007-0302
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发表时间：
2008-09
影响因子：
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通讯作者：
Haipeng Sun;E. Sheveleva;Qin M. Chen
中科院分区：
文献类型：
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作者：
Haipeng Sun;E. Sheveleva;Qin M. Chen
环氧合酶(COX)是前列腺素生物合成的限速酶。虽然COX-1在许多组织中都有结构性表达，但我们发现糖皮质激素可导致心肌细胞COX-1基因表达升高。生理剂量(0.05-1微米)的皮质酮(CT)可诱导COX-1基因的转录激活，核连续和启动子报告分析表明。糖皮质激素受体(GR)拮抗剂米非司酮可阻止CT诱导COX-1。COX-1基因启动子缺失和突变研究表明，Sp转录因子在CT诱导的COX-1基因中起作用。EMSA或染色质免疫沉淀分析表明，GR和SP3转录因子与COX-1基因启动子结合。免疫共沉淀实验发现GR与SP3之间存在关联。小干扰RNA沉默SP3蛋白可抑制CT诱导的COX-1启动子激活。我们的结果提示，激活的GR与SP3转录因子相互作用，与COX-1启动子结合，促进心肌细胞COX-1基因的表达。
Cyclooxygenase (COX) encodes a rate-limiting enzyme in the biosynthesis of prostanoids. Although COX-1 is constitutively expressed in many tissues, we found that glucocorticoids cause elevated expression of COX-1 gene in cardiomyocytes. Corticosterone (CT) at physiologically relevant doses (0.05-1 microm) induces transcriptional activation of COX-1 gene as shown by nuclear run-on and promoter reporter assays. An antagonist of glucocorticoid receptor (GR), mifepristone, prevented CT from inducing COX-1. COX-1 gene promoter deletion and mutation studies indicate a role of Sp transcription factors in CT-induced COX-1 gene. EMSAs or chromatin immunoprecipitation assays suggest that GR and Sp3 transcription factor bind to the promoter of COX-1 gene. Coimmunoprecipitation assays found an association of GR with Sp3. Silencing Sp3 protein with small interfering RNA suppressed CT-induced COX-1 promoter activation. Our data suggest that activated GR interacts with Sp3 transcription factor in binding to COX-1 promoter to enhance COX-1 gene expression in cardiomyocytes.