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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
1
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pubmed:dateCreated |
2009-1-5
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pubmed:abstractText |
Glucocorticoids have major antiinflammatory effects. Because COX-2 is the rate-limiting enzyme for proinflammatory prostaglandins, this study investigated the combinatorial inhibitory role of glucocorticoid receptor (GR) in COX-2 gene induction in macrophages and sought to identify the molecular mechanisms for that inhibition. Glucocorticoid-activated GR repressed COX-2 gene induction by lipopolysaccharide (LPS). Activated GR inhibited LPS-induced activator protein 1 activity, which in turn decreased activating transcription factor 2/c-Jun phosphorylation. The inhibition of MAPK-dependent activating transcription factor 2/c-Jun phosphorylation by GR in COX-2 repression was a result of MAPK phosphatase-1 (MKP-1) induction. Although GR did not inhibit LPS-induced p65 phosphorylation or nuclear factor-kappaB DNA binding activity, deletion of the nuclear factor-kappaB binding site in the COX-2 gene suppressed the ability of glucocorticoid to attenuate COX-2 induction. Chromatin immunoprecipitation and transfection assays revealed that a p65 DNA complex involving GR-bound GR-interacting protein 1 (GRIP1) also contributed to COX-2 repression. Additional knockdown and transfection assays identified other inflammatory genes coordinately regulated by MKP-1 and GRIP1. In summary, activated GR was found to antagonize the LPS-dependent induction of the COX-2 gene via a novel combinatorial mechanism involving MKP-1-mediated activator protein 1 inhibition and GR/GRIP1 recruitment to the p65 DNA complex; moreover, this work facilitated the identification of other GR-responding MKP-1/GRIP1-regulated genes.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Activating Transcription Factor 2,
http://linkedlifedata.com/resource/pubmed/chemical/Adaptor Proteins, Signal Transducing,
http://linkedlifedata.com/resource/pubmed/chemical/Atf2 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Creb1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic AMP Response...,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase 2,
http://linkedlifedata.com/resource/pubmed/chemical/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/Dual Specificity Phosphatase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Dusp1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Grip1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/JNK Mitogen-Activated Protein...,
http://linkedlifedata.com/resource/pubmed/chemical/Lipopolysaccharides,
http://linkedlifedata.com/resource/pubmed/chemical/Macromolecular Substances,
http://linkedlifedata.com/resource/pubmed/chemical/Nerve Tissue Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-jun,
http://linkedlifedata.com/resource/pubmed/chemical/Ptgs2 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Glucocorticoid,
http://linkedlifedata.com/resource/pubmed/chemical/Rela protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factor RelA,
http://linkedlifedata.com/resource/pubmed/chemical/p38 Mitogen-Activated Protein...
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
0888-8809
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
23
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
86-99
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:18945810-Activating Transcription Factor 2,
pubmed-meshheading:18945810-Adaptor Proteins, Signal Transducing,
pubmed-meshheading:18945810-Animals,
pubmed-meshheading:18945810-Base Sequence,
pubmed-meshheading:18945810-Cell Line,
pubmed-meshheading:18945810-Cyclic AMP Response Element-Binding Protein,
pubmed-meshheading:18945810-Cyclooxygenase 2,
pubmed-meshheading:18945810-DNA,
pubmed-meshheading:18945810-Dual Specificity Phosphatase 1,
pubmed-meshheading:18945810-Enzyme Induction,
pubmed-meshheading:18945810-Gene Expression,
pubmed-meshheading:18945810-JNK Mitogen-Activated Protein Kinases,
pubmed-meshheading:18945810-Lipopolysaccharides,
pubmed-meshheading:18945810-Macromolecular Substances,
pubmed-meshheading:18945810-Mice,
pubmed-meshheading:18945810-Models, Biological,
pubmed-meshheading:18945810-Nerve Tissue Proteins,
pubmed-meshheading:18945810-Phosphorylation,
pubmed-meshheading:18945810-Proto-Oncogene Proteins c-jun,
pubmed-meshheading:18945810-Receptors, Glucocorticoid,
pubmed-meshheading:18945810-Transcription Factor RelA,
pubmed-meshheading:18945810-p38 Mitogen-Activated Protein Kinases
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pubmed:year |
2009
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pubmed:articleTitle |
A novel mitogen-activated protein kinase phosphatase-1 and glucocorticoid receptor (GR) interacting protein-1-dependent combinatorial mechanism of gene transrepression by GR.
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pubmed:affiliation |
Innovative Drug Research Center for Metabolic and Inflammatory Disease, College of Pharmacy, Seoul National University, Sillim-dong, Kwanak-gu, Seoul 151-742, Korea.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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