Insulin-like growth factor-1 receptor is regulated by microRNA-133 during skeletal myogenesis.
Insulin-like growth factor-1 receptor is regulated by microRNA-133 during skeletal myogenesis.
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骨骼肌生成过程中胰岛素样生长因子 1 受体受 microRNA-133 调节
DOI：
10.1371/journal.pone.0029173
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Qu LH
中科院分区：
文献类型：
--
作者：
Huang MB;Xu H;Xie SJ;Zhou H;Qu LH
背景胰岛素样生长因子（IGF）信号通路在骨骼肌发育中起着重要作用。然而，人们对基本的监管机制知之甚少。最近，一个大家族的小RNA，命名为microRNA（miRNAs），已被确定为许多发育过程的关键调控因子。由于miRNAs参与多种信号通路的调节，我们推测miRNAs可能参与骨骼肌发生中IGF信号的调节。在本研究中，我们确定细胞表面受体IGF-1 R直接受肌肉特异性miRNA microRNA-133（miR-133）调控。在IGF-1 R的3′非翻译区（3′UTR）发现了一个miR-133保守的功能性结合位点。在C2 C12成肌细胞的分化过程中，IGF-1 R蛋白而不是信使RNA（mRNA）表达逐渐减少，同时miR-133上调。C2 C12细胞中miR-133的过表达显着抑制了转录后水平的IGF-1 R表达。我们还证明了miR-133的过表达和IGF-1 R的敲低都下调了Akt的磷酸化，Akt是PI 3 K/Akt信号通路的中心介质。此外，在C2 C12分化过程中，通过添加IGF-1显著加速了miR-133的上调。从机制上讲，我们发现，肌细胞生成素的表达，肌细胞生成素的转录因子报告反式激活miR-133，增加IGF-1刺激。结论/意义我们的结果阐明了一个负反馈回路，其中IGF-1刺激的miR-133反过来抑制IGF-1 R表达，以调节骨骼肌发生过程中的IGF-1 R信号通路。这些发现也表明miR-133可能是肌肉疾病的潜在治疗靶点。
Background The insulin-like growth factor (IGF) signaling pathway has long been established as playing critical roles in skeletal muscle development. However, the underlying regulatory mechanism is poorly understood. Recently, a large family of small RNAs, named microRNAs (miRNAs), has been identified as key regulators for many developmental processes. Because miRNAs participate in the regulation of various signaling pathways, we hypothesized that miRNAs may be involved in the regulation of IGF signaling in skeletal myogenesis. Methodology/Principal Findings In the present study, we determined that the cell-surface receptor IGF-1R is directly regulated by a muscle-specific miRNA, microRNA-133 (miR-133). A conserved and functional binding site for miR-133 was identified in the 3′untranslated region (3′UTR) of IGF-1R. During differentiation of C2C12 myoblasts, IGF-1R protein, but not messenger RNA (mRNA) expression, was gradually reduced, concurrent with the upregulation of miR-133. Overexpression of miR-133 in C2C12 cells significantly suppressed IGF-1R expression at the posttranscriptional level. We also demonstrated that both overexpression of miR-133 and knockdown of IGF-1R downregulated the phosphorylation of Akt, the central mediator of the PI3K/Akt signaling pathway. Furthermore, upregulation of miR-133 during C2C12 differentiation was significantly accelerated by the addition of IGF-1. Mechanistically, we found that the expression of myogenin, a myogenic transcription factor reported to transactivate miR-133, was increased by IGF-1 stimulation. Conclusion/Significance Our results elucidate a negative feedback circuit in which IGF-1-stimulated miR-133 in turn represses IGF-1R expression to modulate the IGF-1R signaling pathway during skeletal myogenesis. These findings also suggest that miR-133 may be a potential therapeutic target in muscle diseases.
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影响因子：
4.8
作者：
COLEMAN, ME;DEMAYO, F;SCHWARTZ, RJ
通讯作者：
SCHWARTZ, RJ
影响因子：
14.9
作者：
Chen C;Ridzon DA;Broomer AJ;Zhou Z;Lee DH;Nguyen JT;Barbisin M;Xu NL;Mahuvakar VR;Andersen MR;Lao KQ;Livak KJ;Guegler KJ
通讯作者：
Guegler KJ
DOI：
10.1083/jcb.201007165
发表时间：
2011-01-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ge Y;Sun Y;Chen J
通讯作者：
Chen J
影响因子：
16
作者：
Lu, JR;McKinsey, TA;Olson, EN
通讯作者：
Olson, EN
影响因子：
64.5
作者：
BAKER, J;LIU, JP;EFSTRATIADIS, A
通讯作者：
EFSTRATIADIS, A