Gyrd-Hansen Mads, Krag Thomas O B, Rosmarin Alan G, Khurana Tejvir S
Department of Clinical Biochemistry, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark.
J Neurol Sci. 2002 May 15;197(1-2):27-35. doi: 10.1016/s0022-510x(02)00038-2.
Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by the absence of dystrophin. Utrophin is the autosomal homolog of dystrophin and capable of compensating for the absence of dystrophin, when overexpressed. In skeletal muscle, utrophin plays an important role in the formation of neuromuscular junctions. This selective enrichment occurs, in part by transcriptional regulation of the utrophin gene at the sub-synaptic nuclei in muscle. Utrophin's complex transcriptional regulation is not yet fully understood, however, GABP alpha / beta has recently been shown to bind the N box and activate the utrophin promoter in response to heregulin. In this study, we show that the transcription factor Sp1 binds and activates the utrophin promoter in Drosophila S2 cells as well as define a Sp1 response element. We demonstrate that heregulin treatment of cultured muscle cells activates the ERK pathway and phosphorylates serine residue(s) in the consensus ERK recognition site of Sp1. Finally, Sp1 is shown to functionally cooperate with GABP alpha / beta and cause a 58-fold increase of de novo utrophin promoter transcription. Taken together, these findings help define mechanisms used for transcriptional regulation of utrophin expression as well as identify new targets for achieving potentially therapeutic upregulation of utrophin in DMD.
杜氏肌营养不良症（DMD）是一种由肌营养不良蛋白缺失引起的致命性神经肌肉疾病。抗肌萎缩蛋白是肌营养不良蛋白的常染色体同源物，当过度表达时能够补偿肌营养不良蛋白的缺失。在骨骼肌中，抗肌萎缩蛋白在神经肌肉接头的形成中起重要作用。这种选择性富集部分是通过肌肉中突触下核处抗肌萎缩蛋白基因的转录调控实现的。然而，抗肌萎缩蛋白复杂的转录调控尚未完全了解，不过，最近研究表明，GABPα/β可结合N盒并在heregulin的作用下激活抗肌萎缩蛋白启动子。在本研究中，我们发现转录因子Sp1在果蝇S2细胞中结合并激活抗肌萎缩蛋白启动子，同时确定了一个Sp1反应元件。我们证明，用heregulin处理培养的肌肉细胞可激活ERK通路，并使Sp1的共有ERK识别位点中的丝氨酸残基磷酸化。最后，研究表明Sp1与GABPα/β在功能上协同作用，使抗肌萎缩蛋白启动子的从头转录增加58倍。综上所述，这些发现有助于确定抗肌萎缩蛋白表达的转录调控机制，并识别出在DMD中实现抗肌萎缩蛋白潜在治疗性上调的新靶点。
