FKHR (FOXO1a) is required for myotube fusion of primary mouse myoblasts
FKHR (FOXO1a) is required for myotube fusion of primary mouse myoblasts
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DOI：
10.1093/emboj/cdg116
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发表时间：
2003-03-03
期刊：
影响因子：
11.4
通讯作者：
Grosveld, GC
中科院分区：
文献类型：
--
作者：
Bois, PRJ;Grosveld, GC
在各种已建立的细胞系中，转录因子FKHR（人横纹肌肉瘤中的叉头，FOXO 1a）的激活诱导细胞周期停滞，随后是凋亡。这些作用通过激活磷脂酰肌醇3-激酶/Akt途径抑制，导致FKHR磷酸化及其从细胞核输出，从而阻断其促凋亡活性。在这里，我们报告，FKHR调节分化的原代成肌细胞的融合。我们证明，FKHR是本地化的细胞质中的增殖成肌细胞，但易位到细胞核的磷酸化独立的途径后，血清饥饿，诱导成肌细胞分化的条件。终末分化期间FKHR磷酸化似乎下调其融合活性，因为显性活性非磷酸化FKHR突变体显著增加肌管融合的速率和程度。然而，这种FKHR突变体只有在其他事件启动分化过程后才发挥其作用。相反，显性阴性FKHR突变体的强制表达阻断了肌管形成，而野生型FKHR没有影响。我们的结论是，除了FoxO蛋白在调节细胞周期进程和细胞凋亡中的作用外，FKHR还控制肌源性分化过程中肌管融合的速率。
Activation of the transcription factor FKHR (Forkhead in human rhabdomyosarcoma, FOXO1a) in various established cell lines induces cell cycle arrest followed by apoptosis. These effects are inhibited through activation of the phosphatidylinositol 3-kinase/Akt pathway, resulting in FKHR phosphorylation and its export from the nucleus, thus blocking its pro-apoptotic activity. Here we report that FKHR regulates fusion of differentiating primary myoblasts. We demonstrate that FKHR is localized in the cytoplasm of proliferating myoblasts, yet translocates to the nucleus by a phosphorylation-independent pathway following serum starvation, a condition that induces myoblast differentiation. FKHR phosphorylation during terminal differentiation appears to downregulate its fusion activity, as a dominant-active non-phosphorylatable FKHR mutant dramatically augments the rate and extent of myotube fusion. However, this FKHR mutant exerts its effects only after other events initiated the differentiation pro cess. Conversely, enforced expression of a dominant-negative FKHR mutant blocks myotube formation whereas wild-type FKHR has no effect. We conclude that in addition to the role of FoxO proteins in regulating cell cycle progress and apoptosis, FKHR controls the rate of myotube fusion during myogenic differentiation.