E47 phosphorylation by p38 MAPK promotes MyoD/E47 association and muscle-specific gene transcription
E47 phosphorylation by p38 MAPK promotes MyoD/E47 association and muscle-specific gene transcription
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DOI：
10.1038/sj.emboj.7600528
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发表时间：
2005-03-09
期刊：
影响因子：
11.4
通讯作者：
Muñoz-Cánoves, P
中科院分区：
文献类型：
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作者：
Lluís, F;Ballestar, E;Muñoz-Cánoves, P
肌源性基本螺旋环-螺旋（bHLH）转录因子（如MyoD）的异二聚体与普遍存在的bHLH蛋白E12和E47对肌肉基因启动子上的E-box序列的选择性识别是骨骼肌发生中的关键事件。然而，MyoD或E47的同源二聚体不能结合并激活肌肉染色质靶点，这表明功能性MyoD/E47异源二聚体的形成在控制肌肉转录中是关键的。在这里，我们表明，p38 MAPK，其活性是必不可少的肌生成，调节MyoD/E47异源二聚化。p38磷酸化E47的Ser 140诱导MyoD/E47协会和肌肉特异性转录的激活，而不可磷酸化的E47突变体Ser 140 Ala未能与MyoD异源二聚化，并显示受损的肌生成潜力。此外，在肌细胞中抑制p38活性排除了E47在Ser 140处的磷酸化，这导致MyoD/E47异源二聚化减少和肌肉分化效率低下，这是由于转录因子与肌肉基因的E调节区的结合受损。这些发现确定了一种新的促肌生成作用的p38在调节功能性MyoD/E47异二聚体的形成，是必不可少的肌生成。
Selective recognition of the E-box sequences on muscle gene promoters by heterodimers of myogenic basic helix loop - helix ( bHLH) transcription factors, such as MyoD, with the ubiquitous bHLH proteins E12 and E47 is a key event in skeletal myogenesis. However, homodimers of MyoD or E47 are unable of binding to and activating muscle chromatin targets, suggesting that formation of functional MyoD/E47 heterodimers is pivotal in controlling muscle transcription. Here we show that p38 MAPK, whose activity is essential for myogenesis, regulates MyoD/E47 heterodimerization. Phosphorylation of E47 at Ser140 by p38 induces MyoD/E47 association and activation of muscle-specific transcription, while the nonphosphorylatable E47 mutant Ser140Ala fails to heterodimerize with MyoD and displays impaired myogenic potential. Moreover, inhibition of p38 activity in myocytes precludes E47 phosphorylation at Ser140, which results in reduced MyoD/E47 heterodimerization and inefficient muscle differentiation, as a consequence of the impaired binding of the transcription factors to the E regulatory regions of muscle genes. These findings identify a novel pro-myogenic role of p38 in regulating the formation of functional MyoD/E47 heterodimers that are essential for myogenesis.