The Mediator subunit MED1/TRAP220 is required for optimal glucocorticoid receptor-mediated transcription activation.
The Mediator subunit MED1/TRAP220 is required for optimal glucocorticoid receptor-mediated transcription activation.
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DOI：
10.1093/nar/gkm661
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发表时间：
2007
影响因子：
14.9
通讯作者：
Roeder RG
中科院分区：
文献类型：
--
作者：
Chen W;Roeder RG
Mediator的MED 1/TRAP 220亚基在促进该多亚基共激活因子复合物通过其配体结合结构域与核受体的配体依赖性相互作用中起关键作用。分离的MED 1/TRAP 220蛋白先前被证明以配体依赖性方式与糖皮质激素受体（GR）相互作用。然而，MED 1/TRAP 220的功能作用，在整个调解人的背景下，没有很好地研究在GR介导的转录。在这项研究中，我们表明GR直接结合到介体复合物上，MED 1/TRAP 220的两个LXXLL基序都有助于GR的结合。此外，使用完全缺乏MED 1/TRAP 220的Med 1/Trap 220 −/−小鼠胚胎成纤维细胞（MEF）系，我们表明MED 1/TRAP 220增强了GR介导的从基于MMTV启动子的报告基因的转录，并且MED 1/TRAP 220 LXXLL基序中的突变减少了，但不消除GR依赖性转录。对Med 1/Trap 220 −/−细胞中内源性基因的分析证实了不同GR靶基因对MED 1/TRAP 220的不同需求。总之，这些研究结果支持这样的观点，即介导剂，至少部分通过MED 1/TRAP 220，在配体依赖性GR介导的基因表达中发挥协同调节作用。
The MED1/TRAP220 subunit of the Mediator plays a key role in facilitating ligand-dependent interactions of this multisubunit coactivator complex with nuclear receptors through their ligand binding domains. The isolated MED1/TRAP220 protein previously was shown to interact with glucocorticoid receptor (GR) in a ligand-dependent manner. However, the functional role of MED1/TRAP220, within the context of the entire Mediator, is not well studied in GR-mediated transcription. In this study, we show that GR binds directly to the Mediator complex and that both LXXLL motifs of MED1/TRAP220 contribute to its binding to GR. Furthermore, using a Med1/Trap220−/− mouse embryonic fibroblast (MEF) line that lacks entirely MED1/TRAP220, we show that MED1/TRAP220 enhances GR-mediated transcription from an MMTV promoter based-reporter gene and that mutations in the MED1/TRAP220 LXXLL motifs reduce, but do not eliminate, GR-dependent transcription. An analysis of endogenous genes in Med1/Trap220−/− cells has confirmed a variable MED1/TRAP220 requirement for different GR target genes. Taken together, these findings support the idea that Mediator, at least in part through MED1/TRAP220, plays a coregulatory role in ligand-dependent GR-mediated gene expression.
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