Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Androstadienes / pharmacology
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Blotting, Northern
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Blotting, Western
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Cell Differentiation
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Cell Line, Transformed
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Enzyme Inhibitors / pharmacology
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Flow Cytometry
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Gene Expression Regulation
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Gene Expression Regulation, Enzymologic
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Genes, Dominant
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Humans
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Interleukin-15 / metabolism
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Interleukin-15 / physiology*
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Interleukin-2 / metabolism
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Interleukin-2 / physiology*
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Interleukin-2 Receptor beta Subunit
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Intracellular Signaling Peptides and Proteins
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Killer Cells, Natural / metabolism*
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Lymphocytes / metabolism
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3 / metabolism*
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Models, Biological
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Phenotype
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Biosynthesis
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Protein c-ets-1
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-ets
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RNA Processing, Post-Transcriptional
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RNA, Messenger / metabolism
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Receptors, Interleukin / metabolism
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Receptors, Interleukin-2 / metabolism
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Signal Transduction
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Time Factors
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Transcription Factors / metabolism*
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Transfection
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Wortmannin
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Androstadienes
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ETS1 protein, human
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Enzyme Inhibitors
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IL2RB protein, human
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Interleukin-15
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Interleukin-2
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Interleukin-2 Receptor beta Subunit
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Intracellular Signaling Peptides and Proteins
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Proto-Oncogene Protein c-ets-1
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-ets
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RNA, Messenger
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Receptors, Interleukin
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Receptors, Interleukin-2
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Transcription Factors
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MKNK1 protein, human
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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Wortmannin