Martin J F, Li L, Olson E N
Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
J Biol Chem. 1992 Jun 5;267(16):10956-60.
The muscle-specific helix-loop-helix (HLH) proteins myogenin, MyoD, myf5, and MRF4 form hetero-oligomers with ubiquitous HLH proteins encoded by the E2A gene and activate muscle transcription by binding to a DNA sequence known as an E-box (CANNTG). Transforming growth factor-beta (TGF-beta) can inhibit muscle differentiation by silencing the transcription-activating potential of myogenic HLH proteins without affecting their ability to bind DNA. We show that repression by TGF-beta is directed at the basic-HLH motif of myogenin and is independent of E2A products. Using a series of reporter genes as targets for trans-activation by myogenin, transcriptional repression by TGF-beta is also shown to map to the E-box motif and to not require heterologous DNA sequence elements. These results demonstrate that TGF-beta represses muscle-specific transcription through a post-translational mechanism that renders the basic-HLH regions of the myogenic regulators nonfunctional. The selective repression of myogenic HLH proteins by TGF-beta indicates that the TGF-beta signaling system can discriminate between different classes of HLH proteins and implies that myogenic HLH proteins activate muscle-specific transcription through a unique mechanism.
肌肉特异性螺旋-环-螺旋（HLH）蛋白肌细胞生成素、肌分化因子（MyoD）、肌因子5（myf5）和肌肉调节因子4（MRF4）与由E2A基因编码的普遍存在的HLH蛋白形成异源寡聚体，并通过结合一种称为E盒（CANNTG）的DNA序列来激活肌肉转录。转化生长因子-β（TGF-β）可通过使肌源性HLH蛋白的转录激活潜能沉默来抑制肌肉分化，而不影响其结合DNA的能力。我们发现，TGF-β的抑制作用针对肌细胞生成素的碱性-HLH基序，且独立于E2A产物。以一系列报告基因作为肌细胞生成素反式激活的靶标，TGF-β的转录抑制作用也被证明定位于E盒基序，且不需要异源DNA序列元件。这些结果表明，TGF-β通过一种翻译后机制抑制肌肉特异性转录，该机制使肌源性调节因子的碱性-HLH区域失去功能。TGF-β对肌源性HLH蛋白的选择性抑制表明，TGF-β信号系统能够区分不同类别的HLH蛋白，并意味着肌源性HLH蛋白通过一种独特的机制激活肌肉特异性转录。
