MED1 phosphorylation promotes its association with Mediator: Implications for nuclear receptor signaling
MED1 phosphorylation promotes its association with Mediator: Implications for nuclear receptor signaling
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DOI：
10.1128/mcb.02191-07
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发表时间：
2008-06-01
影响因子：
5.3
通讯作者：
Fondell, Joseph D.
中科院分区：
文献类型：
--
作者：
Belakavadi, Madesh;Pandey, Pradeep K.;Fondell, Joseph D.
介体是一种保守的多亚基复合体，在调节转录因子和一般的RNA聚合酶II启动装置之间起着功能接口的作用。MED1是该复合体的关键成分，与核受体和一系列其他基因特异性激活剂结合。矛盾的是，MED1只在总的细胞介体复合体中发现了一小部分，并且调节其与核心复合体结合的机制尚不清楚。在这里，我们报告了丝裂原活化蛋白激酶-细胞外信号调节激酶(MAPK-ERK)对MED1的磷酸化促进其与介体的联系。我们发现MED1直接与MED7亚基结合，并且MED1的ERK磷酸化增强了这种相互作用。有趣的是，我们发现甲状腺激素和类固醇激素都能在体内刺激MED1的磷酸化，并且MED1的磷酸化是其核激素受体辅活化子活性所必需的。最后，我们在体外证明了ERK对MED1的磷酸化增强了甲状腺激素受体依赖的转录。我们的发现表明，MED1的ERK磷酸化是一种调节机制，促进了MED1与Mediator的联系，因此可能促进了核激素的一种新的前馈作用。
Mediator is a conserved multisubunit complex that acts as a functional interface between regulatory transcription factors and the general RNA polymerase II initiation apparatus. MED1 is a pivotal component of the complex that binds to nuclear receptors and a broad array of other gene-specific activators. Paradoxically, MED1 is found in only a fraction of the total cellular Mediator complexes, and the mechanisms regulating its binding to the core complex remain unclear. Here, we report that phosphorylation of MED1 by mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) promotes its association with Mediator. We show that MED1 directly binds to the MED7 subunit and that ERK phosphorylation of MED1 enhances this interaction. Interestingly, we found that both thyroid and steroid hormones stimulate MED1 phosphorylation in vivo and that MED1 phosphorylation is required for its nuclear hormone receptor coactivator activity. Finally, we show that MED1 phosphorylation by ERK enhances thyroid hormone receptor-dependent transcription in vitro. Our findings suggest that ERK phosphorylation of MED1 is a regulatory mechanism that promotes MED1 association with Mediator and, as such, may facilitate a novel feed-forward action of nuclear hormones.