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Molecular Basis for Impaired Muscle Differentiation in Myotonic Dystrophy

机译：肌强直性营养不良的肌肉分化受损的分子基础

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Differentiation of skeletal muscle is affected in myotonic dystrophy (DM) patients. Analysis of cultured myoblasts from DM patients shows that DM myoblasts lose the capability to withdraw from the cell cycle during differentiation. Our data demonstrate that the expression and activity of the proteins responsible for cell cycle withdrawal are altered in DM muscle cells. Skeletal muscle cells from DM patients fail to induce cytoplasmic levels of a CUG RNA binding protein, CUGBP1, while normal differentiated cells accumulate CUGBP1 in the cytoplasm. In cells from normal patients, CUGBP1 up-regulates p21 protein during differentiation. Several lines of evidence show that CUGBP1 induces the translation of p21 via binding to a GC-rich sequence located within the 5′ region of p21 mRNA. Failure of DM cells to accumulate CUGBP1 in the cytoplasm leads to a significant reduction of p21 and to alterations of other proteins responsible for the cell cycle withdrawal. The activity of cdk4 declines during differentiation of cells from control patients, while in DM cells cdk4 is highly active during all stages of differentiation. In addition, DM cells do not form Rb/E2F repressor complexes that are abundant in differentiated cells from normal patients. Our data provide evidence for an impaired cell cycle withdrawal in DM muscle cells and suggest that alterations in the activity of CUGBP1 causes disruption of p21-dependent control of cell cycle arrest.
机译：强直性肌营养不良（DM）患者的骨骼肌分化受到影响。对来自DM患者的培养的成肌细胞的分析表明，DM成肌细胞在分化过程中丧失了退出细胞周期的能力。我们的数据表明负责DM细胞的细胞周期退出的蛋白质的表达和活性发生了改变。 DM患者的骨骼肌细胞无法诱导CUG RNA结合蛋白CUGBP1的细胞质水平，而正常分化的细胞则在细胞质中积累CUGBP1。在正常患者的细胞中，CUGBP1在分化过程中上调了p21蛋白。几条证据表明，CUGBP1通过与位于p21 mRNA 5'区域内的富含GC的序列结合，诱导p21的翻译。 DM细胞未能在细胞质中积累CUGBP1会导致p21显着降低，并导致其他导致细胞周期停滞的蛋白质发生改变。 cdk4的活性在对照患者的细胞分化过程中下降，而在DM细胞中，cdk4在分化的所有阶段都高度活跃。此外，DM细胞不会形成在正常患者的分化细胞中丰富的Rb / E2F阻遏物复合物。我们的数据为DM肌肉细胞的细胞周期退出受损提供了证据，并暗示CUGBP1活性的改变会导致p21依赖性细胞周期停滞控制的破坏。

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