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首页> 外文期刊>Journal of Cellular Physiology >Tumor necrosis factor-?? enhances the transcription of smad ubiquitination regulatory factor 1 in an activating protein-1- and runx2-dependent manner
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Tumor necrosis factor-?? enhances the transcription of smad ubiquitination regulatory factor 1 in an activating protein-1- and runx2-dependent manner

机译：肿瘤坏死因子- ? ?转录的smad泛素化监管因子1在一个激活蛋白1,runx2-dependent方式

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Smad ubiquitination regulatory factor 1 (Smurf1) is an E3 ubiquitin ligase that negatively regulates osteoblast differentiation. Although tumor necrosis factor-?? (TNF-??) has been shown to increase Smurf1 expression, the details of the regulatory mechanisms remain unclear. Here, we investigated the molecular mechanism by which TNF-?? stimulates Smurf1 expression in C2C12 and primary cultured mouse calvarial cells. TNF-?? treatment rapidly induced the activation of NF-??B and MAPKs. Smurf1 induction by TNF-?? was blocked by the inhibition of JNK or ERK, while the inhibition of NF-??B and p38 MAPK had no effect on Smurf1 induction. TNF-?? treatment or c-Jun overexpression enhanced the activity of a luciferase reporter that contained a 2.7kb mouse Smurf1 promoter sequence. Site-directed mutagenesis of the Smurf1 reporter and chromatin immunoprecipitation analysis demonstrated that the activating protein-1 (AP-1) binding motif at -922bp on the mouse Smurf1 promoter mediated TNF-??/JNK/AP-1-stimulated Smurf1 transcription. Interestingly, Smurf1 expression was not observed in Runx2-null mouse calvarial cells. When Runx2 was ectopically expressed in these cells, the basal and TNF-??-induced expression of Smurf1 was restored. Overexpression of Runx2 transactivated the Smurf1 promoter in a dose-dependent manner. Reporter and chromatin immunoprecipitation assays demonstrated that the Runx2-binding motif at -202bp functioned in Runx2-mediated Smurf1 expression. ERK activation by TNF-?? treatment or constitutively active MEK1 overexpression increased Smurf1 expression in a Runx2-dependent manner. These results suggest that the JNK/AP-1 and ERK/Runx2 signaling pathways mediate TNF-??-dependent Smurf1 transcription. J. Cell. Physiol. ? 2012 Wiley Periodicals, Inc.
机译：Smad泛素化调节因子1 (Smurf1)是一个负面的E3泛素连接酶吗调节成骨细胞分化。肿瘤坏死因子- ? ?增加Smurf1表达的细节监管机制尚不清楚。的分子机制研究肿瘤坏死因子- ? ?主要培养小鼠颅顶的细胞。治疗快速诱导激活的NF - ? ?被抑制的物或兵,而抑制NF - ? ?影响Smurf1归纳。c-Jun超表达增强的活动荧光素酶报告包含2.7 kb鼠标Smurf1启动子序列。诱变的Smurf1记者和染色质免疫沉淀反应分析表明,激活蛋白1 (AP-1)绑定的主题-922年英国石油公司在鼠标Smurf1启动子介导肿瘤坏死因子- ? ?有趣的是,Smurf1表达式没有被观察到在老鼠Runx2-null颅顶的细胞。ectopically表示在这些细胞中,是吗基底和TNF - ? ?恢复。剂量依赖性的方式Smurf1启动子。记者和染色质免疫沉淀反应化验证明了Runx2-binding主题-202年英国石油公司运作Runx2-mediated Smurf1表达式。持续活跃MEK1过度增加Smurf1 Runx2-dependent表达式的方式。和ERK / Runx2信号通路进行调解肿瘤坏死因子- ? ?杂志。

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