A feedback circuit between miR-133 and the ERK1/2 pathway involving an exquisite mechanism for regulating myoblast proliferation and differentiation.
A feedback circuit between miR-133 and the ERK1/2 pathway involving an exquisite mechanism for regulating myoblast proliferation and differentiation.
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DOI：
10.1038/cddis.2013.462
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发表时间：
2013-11-28
影响因子：
9
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中科院分区：
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之前的研究发现MiR-133在心肌和骨骼肌中特异性表达。 miR-133家族有两个成员：miR-133a和miR-133b。尽管之前的研究表明miR-133a与肌生成相关，但miR-133调控的信号通路仍不是很清楚。在本研究中，我们通过 Solexa 测序表明 miR-133a 和 miR-133b 在肌生成过程中均上调。我们证实miR-133可以通过调节C2C12细胞中的细胞外信号调节激酶（ERK）信号通路促进成肌细胞分化并抑制细胞增殖。 FGFR1 和 PP2AC 均参与 ERK1/2 通路的信号转导，发现在转录后水平受到 miR-133a 和 miR-133b 的负向调节。此外，还检测到 miR-133 对 ERK1/2 磷酸化的下调。还发现 FGFR1 和 PP2AC 通过特异性 siRNA 抑制 C2C12 分化。此外，我们发现抑制ERK1/2通路活性可以抑制C2C12细胞增殖并促进分化起始，但形成短而小的肌管。此外，我们发现miR-133的表达受到ERK1/2信号通路的负调控。总之，我们证明了 miR-133 在成肌细胞中的作用，并进一步揭示了 miR-133 和 ERK1/2 信号通路之间的新反馈环，涉及调节肌生成的精致机制。
MiR-133 was found to be specifically expressed in cardiac and skeletal muscle in previous studies. There are two members in the miR-133 family: miR-133a and miR-133b. Although previous studies indicated that miR-133a was related to myogenesis, the signaling pathways regulated by miR-133 were still not very clear. In this study, we showed that both miR-133a and miR-133b were upregulated during myogenesis through Solexa sequencing. We confirmed that miR-133 could promote myoblast differentiation and inhibit cell proliferation through the regulation of the extracellular signal-regulated kinase (ERK) signaling pathway in C2C12 cells. FGFR1 and PP2AC, which both participate in signal transduction of the ERK1/2 pathway, were found to be negatively regulated by miR-133a and miR-133b at the post-transcriptional level. Also, downregulation of ERK1/2 phosphorylation by miR-133 was detected. FGFR1 and PP2AC were also found to repress C2C12 differentiation by specific siRNAs. In addition, we found that inhibition of ERK1/2 pathway activity can inhibit C2C12 cell proliferation and promote the initiation of differentiation but form short and small myotubes. Furthermore, we found that the expression of miR-133 was negatively regulated by ERK1/2 signaling pathway. In summary, we demonstrated the role of miR-133 in myoblast and further revealed a new feedback loop between miR-133 and the ERK1/2 signaling pathway involving an exquisite mechanism for regulating myogenesis.