Abstract
MAPK phosphatase-1 (MKP-1) is a protein phosphatase that plays a crucial role in innate immunity. This phosphatase inactivates ERK1/2, which are involved in two opposite functional activities of the macrophage, namely proliferation and activation. Here we found that although macrophage proliferation and activation induce MKP-1 with different kinetics, gene expression is mediated by the proximal promoter sequences localized between -380 and -180 bp. Mutagenesis experiments of the proximal element determined that CRE/AP-1 is required for LPS- or M-CSF-induced activation of the MKP-1 gene. Moreover, the results from gel shift analysis and chromatin immunoprecipitation indicated that c-Jun and CREB bind to the CRE/AP-1 box. The distinct kinetics shown by M-CSF and LPS correlates with the induction of JNK and c-jun, as well as the requirement for Raf-1. The signal transduction pathways that activate the induction of MKP-1 correlate kinetically with induction by M-CSF and LPS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites
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Blotting, Western
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Bone Marrow Cells / cytology
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / metabolism
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Cell Proliferation / drug effects
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Chromatin Immunoprecipitation
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Cyclic AMP Response Element-Binding Protein / metabolism*
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Dual Specificity Phosphatase 1 / genetics*
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Dual Specificity Phosphatase 1 / metabolism
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Electrophoretic Mobility Shift Assay
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Gene Expression / drug effects
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism
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Kinetics
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Lipopolysaccharides / pharmacology*
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Macrophage Activation / drug effects
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Macrophage Colony-Stimulating Factor / pharmacology*
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Macrophages / cytology
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Macrophages / drug effects*
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Macrophages / metabolism
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Mice
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Mice, Inbred BALB C
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Protein Binding
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / metabolism
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Proto-Oncogene Proteins c-raf / genetics
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Proto-Oncogene Proteins c-raf / metabolism
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RNA, Small Interfering / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factor AP-1 / metabolism*
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Transfection
Substances
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Cyclic AMP Response Element-Binding Protein
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Lipopolysaccharides
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Proto-Oncogene Proteins c-jun
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RNA, Small Interfering
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Transcription Factor AP-1
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Macrophage Colony-Stimulating Factor
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Proto-Oncogene Proteins c-raf
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JNK Mitogen-Activated Protein Kinases
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Dual Specificity Phosphatase 1