Induction of terminal differentiation by the c-Jun dimerization protein JDP2 in C2 myoblasts and rhabdomyosarcoma cells
Induction of terminal differentiation by the c-Jun dimerization protein JDP2 in C2 myoblasts and rhabdomyosarcoma cells
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DOI：
10.1074/jbc.m205494200
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发表时间：
2002-10-18
影响因子：
4.8
通讯作者：
Aronheim, A
中科院分区：
文献类型：
--
作者：
Ostrovsky, O;Bengal, E;Aronheim, A
肌细胞分化是转录因子和细胞信号蛋白之间复杂相互作用的结果。增殖的成肌细胞在分化之前必须退出细胞周期。肌肉调节因子和肌细胞增强因子2蛋白家族在促进肌肉细胞分化中发挥着重要作用。相反，促进细胞增殖的 AP-1 转录因子家族成员会拮抗肌肉细胞分化。在这里，我们测试了 c-Jun 二聚化蛋白 JDP2 在肌肉细胞分化中的作用。 JDP2 的内源性表达在 C2C12 成肌细胞和横纹肌肉瘤 (RD) 细胞中被诱导分化。 C2C12 成肌细胞中 JDP2 的异位表达抑制细胞周期进程并诱导自发肌细胞分化。同样，RD 细胞中 JDP2 的组成型表达降低了它们的致瘤特征并恢复了它们分化为肌管的能力。 JDP2 与 12-O-tetradecanoylphorbol-13-acetate 增强并协同作用，诱导 RD 细胞的肌细胞分化。此外，JDP2 在编程分化的 C2 和 RD 细胞中诱导 p38 活性。这是首次证明单个转录因子可以挽救非分化癌细胞系中的生肌程序。我们的结果表明，JDP2 蛋白通过参与细胞周期停滞和生肌程序激活，在促进骨骼肌分化中发挥重要作用。
Muscle cell differentiation is a result of a complex interplay between transcription factors and cell signaling proteins. Proliferating myoblasts must exit from the cell cycle prior to their differentiation. The muscle regulatory factor and myocyte enhancer factor-2 protein families play a major role in promoting muscle cell differentiation. Conversely, members of the AP-1 family of transcription factors that promote cell proliferation antagonize muscle cell differentiation. Here we tested the role of the c-Jun dimerization protein JDP2 in muscle cell differentiation. Endogenous expression of JDP2 was induced in both C2C12 myoblast and rhabdomyosarcoma (RD) cells programmed to differentiate. Ectopic expression of JDP2 in C2C12 myoblast cells inhibited cell cycle progression and induced spontaneous muscle cell differentiation. Likewise, constitutive expression of JDP2 in RD cells reduced their tumorigenic characteristics and restored their ability to differentiate into myotubes. JDP2 potentiated and synergized with 12-O-tetradecanoylphorbol-13-acetate to induce muscle cell differentiation of RD cells. In addition, JDP2 induced p38 activity in both C2 and RD cells programmed to differentiate. This is the first demonstration of a single transcription factor that rescues the myogenic program in an otherwise non-differentiating cancer cell line. Our results indicate that the JDP2 protein plays a major role in promoting skeletal muscle differentiation via its involvement in cell cycle arrest and activation of the myogenic program.