Ubiquitin (UbC) expression in muscle cells is increased by glucocorticoids through a mechanism involving Sp1 and MEK1
Ubiquitin (UbC) expression in muscle cells is increased by glucocorticoids through a mechanism involving Sp1 and MEK1
复制标题
DOI：
10.1074/jbc.m200501200
复制
发表时间：
2002-05-10
影响因子：
4.8
通讯作者：
Price, SR
中科院分区：
文献类型：
--
作者：
Marinovic, AC;Zheng, B;Price, SR
胰岛素依赖型糖尿病和其他分解代谢疾病大鼠中存在的肌肉蛋白catalysts通常与糖皮质激素产生增加和编码泛素-蛋白酶体系统组分的mRNA相关。增加泛蛋白（UbC）表达的机制尚未确定。我们研究了L 6肌细胞中UbC表达的调节，因为地塞米松刺激该基因和泛素-蛋白酶体途径的其他编码组分的转录。体内基因组DNA足迹实验的结果表明，一种蛋白质与Sp1位点结合，该位点与UbC转录起始位点上游50 bp相似;地塞米松改变了这些位点的甲基化模式。Sp1与大鼠或人UbC启动子对应的DNA探针结合，用地塞米松处理细胞会增加这种结合。大鼠和人类UbC启动子的缺失和突变分析与Sp1在糖皮质激素诱导UbC中的重要作用一致。地塞米松诱导的泛素表达被一种Sp1结合抑制剂光辉霉素阻断。UO 126，一种MEK 1的药理学抑制剂，也阻断了地塞米松对UbC转录的激活;转染表达组成型活性AMK 1的L 6细胞表现出增加的UbC启动子活性。因此，糖皮质激素增加UbC在肌肉细胞中的表达，通过一种新的转录机制，涉及Sp1和MEK 1。
The muscle protein catabolism present in rats with insulin-dependent diabetes and other catabolic conditions is generally associated with increased glucocorticoid production and mRNAs encoding components of the ubiquitin-proteasome system. The mechanisms that increase ubiquitin (UbC) expression have not been identified. We studied the regulation of UbC expression in L6 muscle cells because dexamethasone stimulates the transcription of this gene and others encoding components of the ubiquitin-proteasome pathway. Results of in vivo genomic DNA footprinting experiments indicate that a protein(s) binds to Sp1 sites similar to50 bp upstream from the UbC transcription start site; dexamethasone changes the methylation pattern at these sites. Sp1 binds to DNA probes corresponding to the rat or human UbC promoter, and treating cells with dexamethasone increases this binding. Deletion and mutation analyses of the rat and human UbC promoters are consistent with an important role of Sp1 in UbC induction by glucocorticoids. Dexamethasone-induced ubiquitin expression is blocked by mithramycin, an inhibitor of Sp1 binding. UO126, a pharmacologic inhibitor of MEK1, also blocks UbC transcriptional activation by dexamethasone; L6 cells transfected to express constitutively active AMK1 exhibit increased UbC promoter activity. Thus, glucocorticoids increase UbC expression in muscle cells by a novel transcriptional mechanism involving Sp1 and MEK1.