Abstract
Transcription factor CCAAT/enhancer-binding protein-beta (C/EBP-beta) regulates a variety of cellular functions in response to exogenous stimuli. We have reported earlier that C/EBP-beta induces gene transcription through a novel interferon (IFN)-response element called gamma-IFN-activated transcriptional element. We show here that IFN-gamma-induced, C/EBP-beta/gamma-IFN-activated transcriptional element-dependent gene expression is regulated by mixed lineage kinases (MLKs), members of the mitogen-activated protein kinase kinase kinase family. MLK3 appears to activate C/EBP-beta in response to IFN-gamma by a mechanism involving decreased phosphorylation of a specific phosphoacceptor residue, Ser(64), within the transactivation domain. Decreased phosphorylation of Ser(64) was independent of IFN-gamma-stimulated ERK1/2 activation and did not require the ERK phosphorylation site Thr(189) located in regulatory domain 2 of C/EBP-beta. Together these studies provide the first evidence that MLK3 is involved in IFN-gamma signaling and identify a novel mechanism of transcriptional activation by IFN-gamma.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding Sites
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Blotting, Western
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CCAAT-Enhancer-Binding Protein-beta / metabolism*
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Cell Line
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Chromatin Immunoprecipitation
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Enzyme Activation
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Gene Expression Regulation
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Gene Expression Regulation, Enzymologic*
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Green Fluorescent Proteins / metabolism
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Interferon-gamma / metabolism*
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MAP Kinase Kinase Kinases / chemistry*
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MAP Kinase Kinase Kinases / physiology*
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Macrophages / metabolism
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Mice
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Mitogen-Activated Protein Kinase Kinase Kinase 11
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Models, Biological
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Models, Genetic
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Mutation
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Phosphorylation
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Plasmids / metabolism
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Protein Structure, Tertiary
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RNA, Small Interfering / metabolism
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Serine / chemistry
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Signal Transduction
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Time Factors
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Transcription, Genetic
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Transcriptional Activation
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Transfection
Substances
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CCAAT-Enhancer-Binding Protein-beta
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RNA, Small Interfering
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Green Fluorescent Proteins
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Serine
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Interferon-gamma
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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MAP Kinase Kinase Kinases