Muscle LIM protein promotes myogenesis by enhancing the activity of MyoD
Muscle LIM protein promotes myogenesis by enhancing the activity of MyoD
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DOI：
10.1128/mcb.17.8.4750
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发表时间：
1997-08-01
影响因子：
5.3
通讯作者：
Konieczny, SF
中科院分区：
文献类型：
--
作者：
Kong, YF;Flick, MJ;Konieczny, SF
肌肉LIM蛋白(MLP)是一种肌肉特异性LIM蛋白，存在于细胞核和胞浆中，在C2C12成肌细胞中过表达促进骨骼肌发生，而抑制MLP活性则阻碍终末分化。因此，MLP发挥着积极的发育调节作用，尽管MLP促进末端分化事件的机制尚不清楚。在研究与核型和细胞质形式相关的不同角色时，我们发现核MLP通过与肌肉基本螺旋-环-螺旋(BHLH)转录因子MyoD、MRF4和肌生成素的物理相互作用来发挥作用，这种相互作用具有高度的特异性，因为MLP不与非肌肉bHLH蛋白E12或E47或与肌细胞增强因子-2(MEF2)蛋白相关联，后者与肌源性bHLH蛋白协同作用以促进肌肉发生，MLP中的第一个LIM基序和MyoD的高度保守的bHLH区域负责调节这些肌肉特异性因子之间的联系。MLP还与MyoD-E47异二聚体相互作用，导致与这种活性bHLH复合体相关的DNA结合活性增加。尽管MLP缺乏一个功能性转录激活结构域，但我们认为它通过增加与特定DNA调控元件的相互作用而作为肌源性bHLH蛋白的辅助因子，因此，MLP-MyoD-E蛋白的功能复合体揭示了启动和维持成肌程序的新机制，并为LIM-Only蛋白如何控制多种发育途径提供了一种全局策略。
The muscle LIM protein (MLP) is a muscle-specific LIM-only factor that exhibits a dual subcellular localization, being present in both the nucleus and in the cytoplasm, Overexpression of MLP in C2C12 myoblasts enhances skeletal myogenesis, whereas inhibition of MLP activity blocks terminal differentiation. Thus, MLP functions as a positive developmental regulator, although the mechanism through which MLP promotes terminal differentiation events remains unknown. While examining the distinct roles associated with the nuclear and cytoplasmic forms of MLP, we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin, This interaction is highly specific since MLP does not associate with nonmuscle bHLH proteins E12 or E47 or with the myocyte enhancer factor-2 (MEF2) protein, which acts cooperatively with the myogenic bHLH proteins to promote myogenesis, The first LIM motif in MLP and the highly conserved bHLH region of MyoD are responsible for mediating the association between these muscle-specific factors. MLP also interacts with MyoD-E47 heterodimers, leading to an increase in the DNA-binding activity associated with this active bHLH complex. Although MLP lacks a functional transcription activation domain, we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements, Thus, the functional complex of MLP-MyoD-E protein reveals a novel mechanism for both initiating and maintaining the myogenic program and suggests a global strategy for how LIM-only proteins may control a variety of developmental pathways.