Phosphorylation of the human microRNA-generating complex mediates MAPK/Erk signaling.
Phosphorylation of the human microRNA-generating complex mediates MAPK/Erk signaling.
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DOI：
10.1016/j.cell.2009.06.044
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发表时间：
2009-10-02
期刊：
影响因子：
64.5
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Paroo Z;Ye X;Chen S;Liu Q
MicroRNA(MiRNA)控制着越来越多的生物和疾病过程。因此，了解miRNA途径被调控的机制是一个重要的研究领域。我们确定人类miRNA生成复合体由DICER和磷酸-TRBP异构体组成。TRBP的磷酸化是由丝裂原活化蛋白激酶(MAPK)ERK介导的。模拟磷酸的TRBP的表达和TRBP的磷酸化通过增加miRNA生成复合体的稳定性来促进miRNA的合成。促有丝分裂信号对血清和促癌剂PMA的反应依赖于TRBP的磷酸化。伴随着这些效应的是促进生长的miRNA水平的协调增加和let-7肿瘤抑制因子miRNA的表达减少。相反，对MAPK/Erk的药物抑制导致了抑制生长的miRNA图谱。综上所述，这些研究表明，MAPK/Erk途径调节miRNA机制，并提出了一个一般原理，其中信号系统针对miRNA途径实现生物反应。
MicroRNA (miRNA) govern an expanding number of biological and disease processes. Understanding the mechanisms by which the miRNA pathway is regulated, therefore, represents an important area of investigation. We determined that the human miRNA-generating complex is comprised of Dicer and phospho-TRBP isoforms. Phosphorylation of TRBP is mediated by the mitogen activated protein kinase (MAPK) Erk. Expression of phospho-mimic TRBP and TRBP phosphorylation enhanced miRNA production by increasing stability of the miRNA-generating complex. Mitogenic signaling in response to serum and the tumor promoter PMA was dependent on TRBP phosphorylation. These effects were accompanied by a coordinated increase in levels of growth promoting miRNA and reduced expression of let-7 tumor suppressor miRNA. Conversely, pharmacological inhibition of MAPK/Erk resulted in an anti-growth miRNA profile. Taken together, these studies indicate that the MAPK/Erk pathway regulates the miRNA machinery and suggest a general principle, wherein signaling systems target the miRNA pathway to achieve biological responses.
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