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Tytuł:
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Inhibition of glucocorticoid receptor-mediated transcriptional activation by p38 mitogen-activated protein (MAP) kinase.
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Autorzy:
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Szatmáry Z; Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
Garabedian MJ
Vilcek J
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Źródło:
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The Journal of biological chemistry [J Biol Chem] 2004 Oct 15; Vol. 279 (42), pp. 43708-15. Date of Electronic Publication: 2004 Aug 02.
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Typ publikacji:
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Journal Article; Research Support, U.S. Gov't, P.H.S.
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Język:
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English
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Imprint Name(s):
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Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
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MeSH Terms:
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Receptors, Glucocorticoid/*genetics
Transcriptional Activation/*genetics
p38 Mitogen-Activated Protein Kinases/*metabolism
Cloning, Molecular ; Dexamethasone/pharmacology ; Enzyme Activation ; HeLa Cells ; Humans ; MAP Kinase Kinase 6/genetics ; MAP Kinase Kinase 6/metabolism ; Receptors, Glucocorticoid/antagonists & inhibitors ; Receptors, Glucocorticoid/drug effects ; Recombinant Proteins/metabolism ; Transcription, Genetic/genetics ; Transfection
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Grant Information:
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CA75071 United States CA NCI NIH HHS; DK54836 United States DK NIDDK NIH HHS
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Substance Nomenclature:
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0 (Receptors, Glucocorticoid)
0 (Recombinant Proteins)
7S5I7G3JQL (Dexamethasone)
EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
EC 2.7.12.2 (MAP Kinase Kinase 6)
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Entry Date(s):
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Date Created: 20040805 Date Completed: 20041214 Latest Revision: 20210206
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Update Code:
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20240104
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DOI:
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10.1074/jbc.M406568200
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PMID:
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15292225
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Tumor necrosis factor (TNF) promotes certain immune and inflammatory responses, whereas glucocorticoids exert immunosuppressive and anti-inflammatory actions. We show that TNF treatment produced a modest inhibition of glucocorticoid receptor (GR)-mediated transcriptional activation of a mouse mammary tumor virus (MMTV) promoter-driven luciferase construct in HeLa cells. The mitogen-activated protein (MAP) kinases, p38 and c-Jun N-terminal kinase (JNK), are important mediators of target gene activation by TNF, and JNK activation was earlier shown to inhibit GR-mediated transcriptional activation by direct phosphorylation of GR at Ser-246. Transfection of HeLa cells with MKK6b(E), a constitutively active specific upstream activator of p38, led to a potent inhibition of GR activation of the MMTV promoter-driven luciferase construct. A similar inhibition of activation of the MMTV promoter-driven luciferase construct was seen in HeLa cells transfected with MKK7(D), a constitutively functional activator of JNK. Data from "domain swap" experiments using GR chimeras indicated that the main target of the p38-mediated (but not JNK-mediated) inhibition is the ligand-binding domain of GR (spanning amino acids 525-795), whereas the constitutively active N-terminal AF-1 region (spanning amino acids 106-237) is dispensable for the inhibitory effect of p38. We also demonstrate that activated p38 targets the GR ligand-binding domain indirectly. Suppression of GR function by activated p38 and JNK MAP kinases may be physiologically important as a mechanism of resistance to glucocorticoids seen in many patients with chronic inflammatory conditions.