Fine regulation of RhoA and rock is required for skeletal muscle differentiation
Fine regulation of RhoA and rock is required for skeletal muscle differentiation
复制标题
DOI：
10.1074/jbc.m601390200
复制
发表时间：
2006-06-02
影响因子：
4.8
通讯作者：
Falcone, Germana
中科院分区：
文献类型：
--
作者：
Castellani, Loriana;Salvati, Erica;Falcone, Germana
RhoA GTPase控制多种细胞功能，如细胞运动、细胞生长和基因表达。先前的研究表明RhoA介导促进骨骼肌分化的信号输入。我们在这里发现，RhoA蛋白的水平和活性在原代禽类成肌细胞和小鼠卫星细胞分化过程中均下调，这表明需要对该GTPase进行精细调节。此外，激活的RhoA在原代鹌鹑肌细胞中异位表达，而在小鼠肌细胞中不表达，抑制肌肉特异性蛋白的积累和细胞融合。通过使用特定抑制剂破坏RhoA信号传导，我们已经证明，尽管这种GTPase在增殖的成肌细胞中是细胞身份所必需的，但对于最终分化和肌肉基因表达并不是必需的。其下游效应物Rock的激活形式的异位表达会损害鸟类和小鼠成肌细胞的分化。相反，通过特异性抑制剂和小干扰rna介导的基因沉默来抑制Rock，可以加速谱系的进展和增强细胞融合，强调Rock在肌肉形成中的负调节功能。最后，我们报道了Rock独立于RhoA阻止成肌细胞退出细胞周期并致力于分化，并可能接受来自Raf-1激酶的信号输入。
The RhoA GTPase controls a variety of cell functions such as cell motility, cell growth, and gene expression. Previous studies suggested that RhoA mediates signaling inputs that promote skeletal myogenic differentiation. We show here that levels and activity of RhoA protein are down-regulated in both primary avian myoblasts and mouse satellite cells undergoing differentiation, suggesting that a fine regulation of this GTPase is required. In addition, ectopic expression of activated RhoA in primary quail myocytes, but not in mouse myocytes, inhibits accumulation of muscle-specific proteins and cell fusion. By disrupting RhoA signaling with specific inhibitors, we have shown that this GTPase, although required for cell identity in proliferating myoblasts, is not essential for commitment to terminal differentiation and muscle gene expression. Ectopic expression of an activated form of its downstream effector, Rock, impairs differentiation of both avian and mouse myoblasts. Conversely, Rock inhibition with specific inhibitors and small interfering RNA-mediated gene silencing leads to accelerated progression in the lineage and enhanced cell fusion, underscoring a negative regulatory function of Rock in myogenesis. Finally, we have reported that Rock acts independently from RhoA in preventing myoblast exit from the cell cycle and commitment to differentiation and may receive signaling inputs from Raf-1 kinase.