Salisbury Elizabeth, Sakai Keiko, Schoser Benedikt, Huichalaf Claudia, Schneider-Gold Christiane, Nguyen Heather, Wang Gou-Li, Albrecht Jeffrey H, Timchenko Lubov T
Department of Pathology, Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
Exp Cell Res. 2008 Jul 1;314(11-12):2266-78. doi: 10.1016/j.yexcr.2008.04.018. Epub 2008 May 10.
Differentiation of myocytes is impaired in patients with myotonic dystrophy type 1, DM1. CUG repeat binding protein, CUGBP1, is a key regulator of translation of proteins that are involved in muscle development and differentiation. In this paper, we present evidence that RNA-binding activity of CUGBP1 and its interactions with initiation translation complex eIF2 are differentially regulated during myogenesis by specific phosphorylation and that this regulation is altered in DM1. In normal myoblasts, Akt kinase phosphorylates CUGBP1 at Ser28 and increases interactions of CUGBP1 with cyclin D1 mRNA. During differentiation, CUGBP1 is phosphorylated by cyclinD3-cdk4/6 at Ser302, which increases CUGBP1 binding with p21 and C/EBPbeta mRNAs. While cyclin D3 and cdk4 are elevated in normal myotubes; DM1 differentiating cells do not increase these proteins. In normal myotubes, CUGBP1 interacts with cyclin D3/cdk4/6 and eIF2; however, interactions of CUGBP1 with eIF2 are reduced in DM1 differentiating cells and correlate with impaired muscle differentiation in DM1. Ectopic expression of cyclin D3 in DM1 cells increases the CUGBP1-eIF2 complex, corrects expression of differentiation markers, myogenin and desmin, and enhances fusion of DM1 myoblasts. Thus, normalization of cyclin D3 might be a therapeutic approach to correct differentiation of skeletal muscle in DM1 patients.
1型强直性肌营养不良症（DM1）患者的肌细胞分化受损。CUG重复结合蛋白（CUGBP1）是参与肌肉发育和分化的蛋白质翻译的关键调节因子。在本文中，我们提供证据表明，在肌生成过程中，CUGBP1的RNA结合活性及其与起始翻译复合物eIF2的相互作用通过特定的磷酸化受到差异调节，并且这种调节在DM1中发生了改变。在正常成肌细胞中，Akt激酶使CUGBP1的Ser28位点磷酸化，并增加CUGBP1与细胞周期蛋白D1 mRNA的相互作用。在分化过程中，CUGBP1在Ser302位点被细胞周期蛋白D3-cdk4/6磷酸化，这增加了CUGBP1与p21和C/EBPβ mRNA的结合。虽然正常肌管中的细胞周期蛋白D3和cdk4水平升高，但DM1分化细胞中这些蛋白质并未增加。在正常肌管中，CUGBP1与细胞周期蛋白D3/cdk4/6和eIF2相互作用；然而，在DM1分化细胞中，CUGBP1与eIF2的相互作用减少，这与DM1中肌肉分化受损相关。在DM1细胞中异位表达细胞周期蛋白D3可增加CUGBP1-eIF2复合物，纠正分化标志物生肌调节因子和结蛋白的表达，并增强DM1成肌细胞的融合。因此，使细胞周期蛋白D3正常化可能是纠正DM1患者骨骼肌分化的一种治疗方法。
