Abstract
MAPKAP kinase 2 (MK2) is one of several kinases that are regulated through direct phosphorylation by p38 MAP kinase. By introducing a targeted mutation into the mouse MK2 gene, we have determined the physiological function of MK2 in vivo. Mice that lack MK2 show increased stress resistance and survive LPS-induced endotoxic shock. This is due to a reduction of approximately 90% in the production of tumor necrosis factor-alpha (TNF-alpha) and not to a change in signalling from the TNF receptor. The level and stability of TNF-alpha mRNA is not reduced and TNF-alpha secretion is not affected. We conclude that MK2 is an essential component in the inflammatory response which regulates biosynthesis of TNF-alpha at a post-transcriptional level.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cytokines / biosynthesis
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Cytokines / genetics*
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology*
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Inflammation / genetics
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Inflammation / immunology
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides / pharmacology*
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Mice
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Mice, Inbred Strains
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Mice, Knockout
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Mitogen-Activated Protein Kinases / metabolism
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Mutagenesis
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Phosphorylation
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism*
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RNA, Messenger / metabolism
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Restriction Mapping
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Salmonella typhi
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Spleen / immunology
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Transcription, Genetic
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics*
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p38 Mitogen-Activated Protein Kinases
Substances
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Cytokines
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides
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RNA, Messenger
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Tumor Necrosis Factor-alpha
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases