Protein Tyrosine Phosphatase-Like A Regulates Myoblast Proliferation and Differentiation through MyoG and the Cell Cycling Signaling Pathway
Protein Tyrosine Phosphatase-Like A Regulates Myoblast Proliferation and Differentiation through MyoG and the Cell Cycling Signaling Pathway
复制标题
蛋白酪氨酸磷酸酶 A 通过 MyoG 和细胞周期信号通路调节成肌细胞增殖和分化
DOI：
10.1128/mcb.05484-11
复制
发表时间：
2012-01-01
影响因子：
5.3
通讯作者：
Chang, Jiang
中科院分区：
文献类型：
--
作者：
Lin, Xi;Yang, Xiangsheng;Chang, Jiang
摘要 蛋白酪氨酸磷酸酶样 A (PTPLa) 与骨骼肌生成和心脏生成有关。 PTPLa 突变与人类致心律失常性右心室发育不良和犬先天性中心核肌病伴严重肌张力低下相关。 PTPLa 在肌生成中的分子机制尚不清楚。在本报告中，我们证明 PTPLa 是成肌细胞生长和分化所必需的。缺乏 PTPLa 的细胞仍然不成熟，无法分化成成熟的肌管。 MyoG 表达受抑制是成肌细胞分化受损的原因。同时，在 PTPLa 缺陷的成肌细胞中观察到细胞生长受阻，具有明显的 S 期停滞和 G2/M 转变受损。进一步的研究表明，细胞周期蛋白 D1 和细胞周期蛋白 E2 复合物的上调，以及由于 CDK1（细胞周期蛋白依赖性激酶 1）活性降低和 p21 上调导致的 G2/M 转变受损，导致突变细胞 S 期停滞，最终导致细胞生长迟缓。最后，探讨了PTPLa基因的转录调控。我们将 PTPLa 确定为血清反应因子 (SRF) 的新靶基因。骨骼肌和心肌特异性 SRF 敲除导致 PTPLa 表达显着降低，表明小鼠中 PTPLa 基因的转录调控是保守的。
ABSTRACT Protein tyrosine phosphatase-like A (PTPLa) has been implicated in skeletal myogenesis and cardiogenesis. Mutations in PTPLa correlated with arrhythmogenic right ventricular dysplasia in humans and congenital centronuclear myopathy with severe hypotonia in dogs. The molecular mechanisms of PTPLa in myogenesis are unknown. In this report, we demonstrate that PTPLa is required for myoblast growth and differentiation. The cells lacking PTPLa remained immature and failed to differentiate into mature myotubes. The repressed MyoG expression was responsible for the impaired myoblast differentiation. Meanwhile, impeded cell growth, with an obvious S-phase arrest and compromised G2/M transition, was observed in PTPLa-deficient myoblasts. Further study demonstrated that the upregulation of cyclin D1 and cyclin E2 complexes, along with a compromised G2/M transition due to the decreased CDK1 (cyclin-dependent kinase 1) activity and upregulated p21, contributed to the mutant cell S-phase arrest and eventually led to the retarded cell growth. Finally, the transcriptional regulation of the PTPLa gene was explored. We identified PTPLa as a new target gene of the serum response factor (SRF). Skeletal- and cardiac-muscle-specific SRF knockouts resulted in significant decreases in PTPLa expression, suggesting a conserved transcriptional regulation of the PTPLa gene in mice.