Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
J Biol Chem. 2011 Feb 25;286(8):6017-26. doi: 10.1074/jbc.M110.197921. Epub 2010 Dec 13.
IFNγ exhibits potent antitumor effects and plays important roles in the innate immunity against cancer. However, the mechanisms accounting for the antiproliferative effects of IFNγ still remain to be elucidated. We examined the role of Mnk1 (MAPK-interacting protein kinase 1) in IFNγ signaling. Our data demonstrate that IFNγ treatment of sensitive cells results in engagement of Mnk1, activation of its kinase domain, and downstream phosphorylation of the cap-binding protein eIF4E on Ser-209. Such engagement of Mnk1 plays an important role in IFNγ-induced IRF-1 (IFN regulatory factor 1) gene mRNA translation/protein expression and is essential for generation of antiproliferative responses. In studies aimed to determine the role of Mnk1 in the induction of the suppressive effects of IFNs on primitive hematopoietic progenitors, we found that siRNA-mediated Mnk1/2 knockdown results in partial reversal of the suppressive effects of IFNγ on human CD34+-derived myeloid (CFU-GM) and erythroid (BFU-E) progenitors. These findings establish a key role for the Mnk/eIF4E pathway in the regulatory effects of IFNγ on normal hematopoiesis and identify Mnk kinases as important elements in the control of IFNγ-inducible ISG mRNA translation.
IFNγ 具有强大的抗肿瘤作用，并在癌症的先天免疫中发挥重要作用。然而，IFNγ 抑制增殖作用的机制仍有待阐明。我们研究了 Mnk1（MAPK 相互作用蛋白激酶 1）在 IFNγ 信号转导中的作用。我们的数据表明，IFNγ 处理敏感细胞会导致 Mnk1 的结合，其激酶结构域的激活，以及下游 cap 结合蛋白 eIF4E 在 Ser-209 上的磷酸化。Mnk1 的这种结合在 IFNγ 诱导的 IRF-1（IFN 调节因子 1）基因 mRNA 翻译/蛋白表达中起着重要作用，并且是产生抗增殖反应所必需的。在旨在确定 Mnk1 在诱导 IFNs 对原始造血祖细胞的抑制作用中的作用的研究中，我们发现，siRNA 介导的 Mnk1/2 敲低导致 IFNγ 对人 CD34+衍生的髓系（CFU-GM）和红系（BFU-E）祖细胞的抑制作用部分逆转。这些发现确立了 Mnk/eIF4E 途径在 IFNγ 对正常造血的调节作用中的关键作用，并确定 Mnk 激酶是控制 IFNγ 诱导的 ISG mRNA 翻译的重要因素。
