Signaling by p38 MAPK stimulates nuclear localization of the microprocessor component p68 for processing of selected primary microRNAs.
Signaling by p38 MAPK stimulates nuclear localization of the microprocessor component p68 for processing of selected primary microRNAs.
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p38 MAPK 信号传导刺激微处理器组件 p68 的核定位，以处理选定的初级 MicroRNA
DOI：
10.1126/scisignal.2003706
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发表时间：
2013-03-12
影响因子：
7.3
通讯作者：
Huang S
中科院分区：
文献类型：
--
作者：
Hong S;Noh H;Chen H;Padia R;Pan ZK;Su SB;Jing Q;Ding HF;Huang S
microRNA 加工的早期步骤取决于 p38 丝裂原激活蛋白激酶下游的信号传导。促进 MicroRNA 的产生 MicroRNA (miRNA) 是一种小型非编码 RNA，它们以特定 mRNA 为目标进行降解或阻止其翻译，从而导致特定基因产物的敲低。 miRNA 的转录后生成需要含有 Drosha 的复合物成分对初级 miRNA (pri-miRNA) 进行核加工，然后由 Dicer 复合物对所得前体 miRNA (pre-miRNA) 进行胞质加工，以生成成熟 miRNA。洪等人。发现抑制丝裂原激活蛋白激酶 (MAPK) p38 及其效应激酶 MK2 会阻断 pri-miRNA 子集的加工。在细胞质中，MK2 磷酸化 Drosha 复合体成分 p68，这是其易位到细胞核进行 pri-miRNA 加工所必需的。抑制细胞中的 p38 信号传导会减少 miR-145 的产生，而 miR-145 的目标是编码 c-Myc 的 mRNA，从而导致 c-Myc 丰度增加并增强增殖。总之，这些数据表明，p38 MAPK 信号传导是通过促进 p68 的核定位来实现选定 miRNA 生物发生所必需的。 microRNA (miRNA) 在生物和疾病过程中的重要性需要更好地了解调节 miRNA 丰度的机制。我们发现丝裂原激活蛋白激酶 (MAPK) p38 及其下游效应激酶 MAPK 激活蛋白激酶 2 (MK2) 的活性对于初级 miRNA (pri-miRNA) 子集的有效加工是必需的。通过酵母双杂交筛选，我们鉴定了 p68（也称为 DDX5），它是处理 pri-miRNA 的 Drosha 复合体的关键成分，是一种 MK2 相互作用蛋白，并且我们发现 MK2 在细胞中磷酸化了 p68 Ser197。在用 p38 抑制剂处理的野生型小鼠胚胎成纤维细胞 (MEF) 或 MK2 缺陷 (MK2−/−) MEF 中，磷酸模拟突变体 p68 的表达完全恢复了 pri-miRNA 加工，表明 MK2 介导的 p68 磷酸化对于这一过程至关重要。我们发现，虽然 p68 存在于野生型 MEF 的细胞核中，但它主要存在于 MK2−/− MEF 的细胞质中。 p68 的核定位依赖于 MK2 介导的 Ser197 磷酸化。此外，抑制 p38 MAPK 通过抑制靶向 c-Myc 的 miRNA miR-145 的生物发生来增强 c-Myc 的丰度，从而促进野生型 MEF 和乳腺癌 MCF7 细胞的生长。由于 pri-miRNA 加工发生在细胞核中，我们的研究结果表明 p38 MAPK-MK2 信号通路通过促进 p68 的核定位来促进 miRNA 生物合成。
An early step in microRNA processing depends on signaling downstream of the p38 mitogen-activated protein kinase. Promoting MicroRNA Production MicroRNAs (miRNAs) are small noncoding RNAs that target specific mRNAs for degradation or block their translation, thus leading to knockdown of given gene products. Posttranscriptional generation of miRNAs requires the nuclear processing of primary miRNAs (pri-miRNAs) by components of the Drosha-containing complex followed by the cytosolic processing of the resulting precursor miRNAs (pre-miRNAs) by the Dicer complex to generate mature miRNAs. Hong et al. found that inhibition of the mitogen-activated protein kinase (MAPK) p38 and its effector kinase MK2 blocked the processing of a subset of pri-miRNAs. In the cytosol, MK2 phosphorylated the Drosha complex component p68, which was required for its translocation to the nucleus for pri-miRNA processing. Inhibition of p38 signaling in cells decreased the production of miR-145, which targets the mRNA encoding c-Myc, resulting in increased c-Myc abundance and enhanced proliferation. Together, these data suggest that p38 MAPK signaling is required for selected miRNA biogenesis by promoting the nuclear localization of p68. The importance of microRNAs (miRNAs) in biological and disease processes necessitates a better understanding of the mechanisms that regulate miRNA abundance. We showed that the activities of the mitogen-activated protein kinase (MAPK) p38 and its downstream effector kinase MAPK-activated protein kinase 2 (MK2) were necessary for the efficient processing of a subset of primary miRNAs (pri-miRNAs). Through yeast two-hybrid screening, we identified p68 (also known as DDX5), a key component of the Drosha complex that processes pri-miRNAs, as an MK2-interacting protein, and we found that MK2 phosphorylated p68 at Ser197 in cells. In wild-type mouse embryonic fibroblasts (MEFs) treated with a p38 inhibitor or in MK2-deficient (MK2−/−) MEFs, expression of a phosphomimetic mutant p68 fully restored pri-miRNA processing, suggesting that MK2-mediated phosphorylation of p68 was essential for this process. We found that, whereas p68 was present in the nuclei of wild-type MEFs, it was found mostly in the cytoplasm of MK2−/− MEFs. Nuclear localization of p68 depended on MK2-mediated phosphorylation of Ser197. In addition, inhibition of p38 MAPK promoted the growth of wild-type MEFs and breast cancer MCF7 cells by enhancing the abundance of c-Myc through suppression of the biogenesis of the miRNA miR-145, which targets c-Myc. Because pri-miRNA processing occurs in the nucleus, our findings suggest that the p38 MAPK–MK2 signaling pathway promotes miRNA biogenesis by facilitating the nuclear localization of p68.
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