Phosphorylation of Ago2 and Subsequent Inactivation of let-7a RNP-Specific MicroRNAs Control Differentiation of Mammalian Sympathetic Neurons
Phosphorylation of Ago2 and Subsequent Inactivation of let-7a RNP-Specific MicroRNAs Control Differentiation of Mammalian Sympathetic Neurons
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DOI：
10.1128/mcb.00054-16
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发表时间：
2016-04-01
影响因子：
5.3
通讯作者：
Bhattacharyya, Suvendra Nath
中科院分区：
文献类型：
--
作者：
Patranabis, Somi;Bhattacharyya, Suvendra Nath
MicroRNAs(MiRNAs)是一种小的调控RNA，通过与动物细胞中的靶mRNAs进行碱基配对，在转录后调节基因表达。KRAS是一种已知被let-7a miRNAs抑制的癌基因，它在哺乳动物交感神经元和PC12细胞的分化中是必需的。我们记录了在这个分化过程中let-7a活性的丧失，而let-7a miRNA的细胞水平没有任何明显的变化。然而，Ago2是与miRNAs结合形成RNP特异性miRNA(MiRNP)复合体的重要成分，随着神经元的分化，Ago2的水平呈上升趋势。在本研究中，注意到分化诱导的磷酸化和随后来自Ago2的miRNA的丢失，这是分化神经元中miRNA活性丧失的原因。神经元分化诱导丝裂原活化蛋白激酶p38及其下游的丝裂原和应激活化蛋白激酶1(MSK1)的磷酸化。这反过来上调了Ago2的磷酸化，并确保了神经细胞中miRNA与Ago2的解离。MSK1介导的miRNP失活是神经细胞分化的先决条件，其中let-7a miRNA从Ago2上卸载，以确保let-7a靶点KRAS的上调。我们注意到，let-7a的失活对于交感神经元的分化既是必要的也是充分的。
MicroRNAs (miRNAs) are small regulatory RNAs that regulate gene expression posttranscriptionally by base pairing to the target mRNAs in animal cells. KRas, an oncogene known to be repressed by let-7a miRNAs, is expressed and needed for the differentiation of mammalian sympathetic neurons and PC12 cells. We documented a loss of let-7a activity during this differentiation process without any significant change in the cellular level of let-7a miRNA. However, the level of Ago2, an essential component that is associated with miRNAs to form RNP-specific miRNA (miRNP) complexes, shows an increase with neuronal differentiation. In this study, differentiation-induced phosphorylation and the subsequent loss of miRNA from Ago2 were noted, and these accounted for the loss of miRNA activity in differentiating neurons. Neuronal differentiation induces the phosphorylation of mitogen-activated protein kinase p38 and the downstream kinase mitogen-and stress-activated protein kinase 1 (MSK1). This in turn upregulates the phosphorylation of Ago2 and ensures the dissociation of miRNA from Ago2 in neuronal cells. MSK1-mediated miRNP inactivation is a prerequisite for the differentiation of neuronal cells, where let-7a miRNA gets unloaded from Ago2 to ensure the upregulation of KRas, a target of let-7a. We noted that the inactivation of let-7a is both necessary and sufficient for the differentiation of sympathetic neurons.