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Cell Cycle Withdrawal Promotes Myogenic Induction of Akt, a Positive Modulator of Myocyte Survival

机译:退出细胞周期可促进Akt的成肌诱导,Akt是心肌细胞存活的积极调节剂。

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During myogenesis, proliferating myoblasts withdraw from the cell cycle, acquire an apoptosis-resistant phenotype, and differentiate into myotubes. Previous studies indicate that myogenic induction of the cyclin-dependent kinase inhibitor p21 results in an inhibition of apoptotic cell death in addition to its role as a negative cell cycle regulator. Here we demonstrate that the protein encoded by theAkt proto-oncogene is induced in C2C12 cells during myogenic differentiation with a corresponding increase in kinase activity. In differentiating cultures, expression of dominant-negative forms of Akt increase the frequency of cell death whereas expression of wild-type Akt protects against death, indicating that Akt is a positive modulator of myocyte survival. Antisense oligonucleotides against p21 block cell cycle withdrawal, inhibit Akt induction, and enhance cell death in differentiating myocyte cultures. Adenovirus-mediated transfer of wild-type or constitutively active Akt constructs confer partial resistance to cell death under conditions where cell cycle exit is blocked by the antisense oligonucleotides. Collectively, these data indicate that cell cycle withdrawal facilitates the induction of Akt during myogenesis, promoting myocyte survival.
机译:在成肌过程中,增殖的成肌细胞退出细胞周期,获得抗凋亡的表型,并分化为肌管。先前的研究表明,细胞周期蛋白依赖性激酶抑制剂p21的肌原性诱导除其作为负细胞周期调节剂的作用外,还导致凋亡细胞死亡的抑制。在这里,我们证明由 Akt 原癌基因编码的蛋白质在成肌分化过程中在C2C12细胞中被诱导,并相应地增加了激酶活性。在分化的文化中,显性阴性形式的Akt的表达会增加细胞死亡的频率,而野生型Akt的表达可防止死亡,这表明Akt是心肌细胞存活的积极调节剂。针对p21的反义寡核苷酸可阻止细胞周期退出,抑制Akt诱导并增强分化心肌细胞培养物中的细胞死亡。在反义寡核苷酸阻断细胞周期退出的条件下,腺病毒介导的野生型或组成型活性Akt构建体的转移赋予细胞死亡部分抗性。总的来说,这些数据表明细胞周期的撤回促进了在成肌过程中对Akt的诱导,从而促进了肌细胞的存活。

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