Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses
Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses
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DOI：
10.1073/pnas.0900562106
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发表时间：
2009-07-21
影响因子：
11.1
通讯作者：
Platanias, Leonidas C.
中科院分区：
文献类型：
--
作者：
Joshi, Sonali;Kaur, Surinder;Platanias, Leonidas C.
我们提供的证据表明，存在一个干扰素调节的细胞通路，涉及丝裂原活化蛋白激酶（MAPK）整合激酶（Mnk）1。我们的数据表明，I型（α，β）干扰素诱导磷酸化/激活的Mnk 1，这反过来又调节磷酸化的真核起始因子4 E（eIF 4 E）的Ser-209。这种Mnk激活依赖于上游的Jak 1的参与，并需要下游的Mek/Erk MAPK通路的激活。在使用双Mnk 1-/-Mnk 2-/-敲除小鼠胚胎成纤维细胞（MEFs）的研究中，我们发现Mnk激酶的参与对于Isg 15和Isg 54基因的mRNA翻译是必不可少的，这表明该途径在IFN刺激基因（ISG）的mRNA翻译中起重要作用。重要的是，我们的数据表明，药理学抑制Mnk激酶或siRNA介导的敲低Mnk 1和Mnk 2的结果在部分逆转IFN α对正常和白血病造血祖细胞的抑制作用，建立了一个关键作用，这一途径的生成的生长抑制作用的I型IFN。总之，我们的研究结果表明，Mnk/eIF 4 E激酶途径以IFN诱导的方式激活，并在ISG的mRNA翻译和IFN诱导的抗增殖反应的产生中发挥重要作用。
We provide evidence for the existence of an IFN-regulated cellular pathway involving the mitogen-activated protein kinase (MAPK)-integrating kinase (Mnk) 1. Our data demonstrate that type I (alpha, beta) IFNs induce phosphorylation/activation of Mnk1, which, in turn, regulates phosphorylation of the eukaryotic initiation factor 4E (eIF4E) on Ser-209. Such Mnk activation depends on upstream engagement of Jak1, and requires downstream activation of the Mek/Erk MAPK pathway. In studies using double Mnk1-/- Mnk2-/- knockout mouse embryonic fibroblasts (MEFs), we found that engagement of Mnk kinases is essential for mRNA translation of the Isg15 and Isg54 genes, suggesting an important role for this pathway in mRNA translation of IFN-stimulated genes (ISGs). Importantly, our data demonstrate that pharmacological inhibition of Mnk kinases or siRNA-mediated knockdown of Mnk1 and Mnk2 results in partial reversal of the suppressive effects of IFN alpha on normal and leukemic hematopoietic progenitors, establishing a key role for this pathway in the generation of the growth inhibitory effects of type I IFNs. Together, our findings establish that the Mnk/eIF4E kinase pathway is activated in an IFN-inducible manner and plays important roles in mRNA translation for ISGs and generation of IFN-inducible antiproliferative responses.