Interleukins 2 and 15 regulate Ets1 expression via ERK1/2 and MNK1 in human natural killer cells

被引:29
作者
Grund, EM
Spyropoulos, DD
Watson, DK
Muise-Helmericks, RC
机构
[1] Med Univ S Carolina, Hollings Canc Ctr 320, Dept Cell Biol & Anat, Charleston, SC 29425 USA
[2] Med Univ S Carolina, Hollings Canc Ctr 320, Dept Pathol & Lab Med, Charleston, SC 29425 USA
[3] Med Univ S Carolina, Hollings Canc Ctr 320, Dept Biochem & Mol Biol, Charleston, SC 29425 USA
关键词
D O I
10.1074/jbc.M408356200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Interleukins (IL)-2 and IL-15 regulate natural killer (NK) cell proliferation, survival, and cytolytic activity. Ets1 is a transcription factor expressed early in NK cell differentiation. Because IL-2Rbeta, IL-2Rgamma, IL-15, and Ets1 knock-out mice similarly lack NK cells, we explored a molecular connection between IL-2R signaling and Ets1. Here we report the post-transcriptional regulation of Ets1 by IL-2R signaling in human NK cells. IL-2 and IL-15 stimulation leads to increased Ets1 protein levels with no significant change in mRNA levels. Pulse and pulse-chase experiments show that IL-2 stimulation results in both a marked increase in the nascent translation of Ets1 and an increased protein half-life. Pharmacological inhibition of MEK specifically blocks IL-2- and IL-15-induced translation, whereas p38, phosphatidylinositol 3-kinase, and mTOR inhibitors had no effect on Ets1 levels. Fli1, an Ets family member, exhibited a different mechanism of regulation, illustrating the specificity of IL-2R beta and gamma subunit signaling on the regulation of Ets1 expression. Expression of a dominant negative form of MNK1, a regulator of the translation initiation factor eIF4E, blocks the expression of Ets1 as do the dominant negative forms of the common IL-2R beta and gamma chains. Expression of Ets1 is regulated similarly in normal peripheral human NK cells. Taken together, our findings provide a direct link between IL-2R subunit signaling and Ets1 expression and helps to explain the interdependence of the IL-2R subunits and Ets1 for NK cell development and function.
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页码:4772 / 4778
页数:7
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