TGF-β inhibits muscle differentiation through functional repression of myogenic transcription factors by Smad3
TGF-β inhibits muscle differentiation through functional repression of myogenic transcription factors by Smad3
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DOI：
10.1101/gad.925901
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发表时间：
2001-11-15
影响因子：
10.5
通讯作者：
Derynck, R
中科院分区：
文献类型：
--
作者：
Liu, D;Black, BL;Derynck, R
转化生长因子-β（TGF-β）是骨骼肌分化的有效抑制剂，但导致这种抑制的分子机制和信号传导事件的特征很差。在这里，我们表明，TGF-β细胞内效应Smad 3，而不是Smad 2，介导抑制MyoD表达的C3 H10 T12细胞和C2 C12成肌细胞的成肌分化抑制MyoD家族的转录因子的活性。Smad 3介导的抑制作用针对肌肉基因增强子内的E-box序列基序和MyoD的bHLH区域，MyoD与E蛋白伴侣如E12和E47相关联所需的结构域。抑制可以通过提供过量的E12来克服，并且E47与MyoD的共价连接使得E-box依赖性转录活性对Smad 3和TGF-β的作用不敏感。Smad 3与MyoD的HLH结构域物理相互作用，并且这种相互作用与Smad 3干扰MyoD/E蛋白异源二聚化和MyoD复合物与寡聚化E-box位点结合的能力相关。总之，这些结果揭示了TGF-β如何通过Smad 3介导的转录抑制抑制肌源性分化的模型。
Transforming growth factor-beta (TGF-beta) is a potent inhibitor of skeletal muscle differentiation, but the molecular mechanism and signaling events that lead to this inhibition are poorly characterized. Here we show that the TGF-beta intracellular effector Smad3, but not Smad2, mediates the inhibition of myogenic differentiation in MyoD-expressing C3H10T1/2 cells and C2C12 myoblasts by repressing the activity of the MyoD family of transcriptional factors. The Smad3-mediated repression was directed at the E-box sequence motif within muscle gene enhancers and the bHLH region of MyoD, the domain required for its association with E-protein partners such as E12 and E47. The repression could be overcome by supplying an excess of E12, and covalent tethering of E47 to MyoD rendered the E-box-dependent transcriptional activity refractory to the effects of Smad3 and TGF-beta. Smad3 physically interacted with the HLH domain of MyoD, and this interaction correlated with the ability of Smad3 to interfere with MyoD/E protein heterodimerization and binding of MyoD complexes to oligomerized E-box sites. Together, these results reveal a model for how TGF-beta, through Smad3-mediated transcriptional repression, inhibits myogenic differentiation.