The mitogen-activated protein kinase cascade promotes myoblast cell survival by stabilizing the cyclin-dependent kinase inhibitor, p21WAF1 protein
The mitogen-activated protein kinase cascade promotes myoblast cell survival by stabilizing the cyclin-dependent kinase inhibitor, p21WAF1 protein
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DOI：
10.1074/jbc.m211357200
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发表时间：
2003-06-06
影响因子：
4.8
通讯作者：
Bengal, E
中科院分区：
文献类型：
--
作者：
Ostrovsky, O;Bengal, E
在肌发生过程中，增殖的成肌细胞退出细胞周期，并通过程序性细胞死亡或分化成成熟的肌管而被消除。以往的研究表明，丝裂原活化蛋白激酶（MAPK）的活性显着诱导的开始终末分化的C2成肌细胞。我们研究了MAPK通路在C2成肌细胞分化中所起的作用。通过表达活性Raf 1-雌激素受体嵌合体蛋白特异性激活MAPK显著减少了在分化培养基中经历程序性细胞死亡的成肌细胞的数量。Raf 1的激活阻止了分化过程中促凋亡caspase 9蛋白的蛋白水解激活。Raf 1的抗凋亡功能与p21（WAF 1）蛋白的积累相关，这是由于其稳定性增加。p21的反义表达用于确定p21（WAF 1）蛋白是否介导Raf 1的抗凋亡活性。肌细胞中p21（WAF 1）蛋白的减少取消了MAPK通路的抗凋亡活性。我们的结论是，MAPK有助于肌肉分化，防止分化成肌细胞的凋亡细胞死亡，这种活性是由稳定的p21（WAF 1）蛋白介导的。
During myogenesis, proliferating myoblasts withdraw from the cell cycle and are either eliminated by programmed cell death or differentiate into mature myotubes. Previous studies indicate that mitogen-activated protein kinase ( MAPK) activity is significantly induced with the onset of terminal differentiation of C2 myoblasts. We have investigated the part played by the MAPK pathway in the differentiation of C2 myoblasts. Specific activation of MAPK by expression of an active Raf1-estrogen receptor chimera protein reduced significantly the number of myoblasts undergoing programmed cell death in the differentiation medium. Activation of Raf1 prevented the proteolytic activation of the proapoptotic caspase 9-protein during differentiation. The antiapoptotic function of Raf1 correlated with accumulation of the p21(WAF1) protein resulting from its increased stability. Antisense expression of p21 was used to determine whether the p21(WAF1) protein mediated the antiapoptotic activity of Raf1. Reduction of p21(WAF1) protein in muscle cells abolished the antiapoptotic activity of the MAPK pathway. We conclude that MAPK contributes to muscle differentiation by preventing apoptotic cell death of differentiating myoblasts and that this activity is mediated by stabilization of the p21(WAF1) protein.