Source:http://linkedlifedata.com/resource/pubmed/id/11555652
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
46
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pubmed:dateCreated |
2001-11-12
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pubmed:abstractText |
Ligand-dependent down-regulation of the glucocorticoid receptor (GR) has been shown to limit hormone responsiveness, but the mechanisms involved in this process are poorly understood. The glucocorticoid receptor is a phosphoprotein that upon ligand binding becomes hyperphosphorylated, and recent evidence indicates that phosphorylation status of the glucocorticoid receptor plays a prominent role in receptor protein turnover. Because phosphorylation is a key signal for ubiquitination and proteasomal catabolism of many proteins, we evaluated whether the ubiquitin-proteasomal pathway had a role in glucocorticoid receptor down-regulation and the subsequent transcriptional response to glucocorticoids. Pretreatment of COS-1 cells expressing mouse glucocorticoid receptor with the proteasome inhibitor MG-132 effectively blocks glucocorticoid receptor protein down-regulation by the glucocorticoid dexamethasone. Interestingly, both MG-132 and a second proteasome inhibitor beta-lactone significantly enhanced hormone response of transfected mouse glucocorticoid receptor toward transcriptional activation of glucocorticoid receptor-mediated reporter gene expression. The transcriptional activity of the endogenous human glucocorticoid receptor in HeLa cells was also enhanced by MG-132. Direct evidence for ubiquitination of the glucocorticoid receptor was obtained by immunoprecipitation of cellular extracts from proteasome-impaired cells. Examination of the primary sequence of mouse, human, and rat glucocorticoid receptor has identified a candidate PEST degradation motif. Mutation of Lys-426 within this PEST element both abrogated ligand-dependent down-regulation of glucocorticoid receptor protein and simultaneously enhanced glucocorticoid receptor-induced transcriptional activation of gene expression. Unlike wild type GR, proteasomal inhibition failed to enhance significantly transcriptional activity of K426A mutant GR. Together these findings suggest a major role of the ubiquitin-proteasome pathway in regulating glucocorticoid receptor protein turnover, thereby providing a mechanism to terminate glucocorticoid responses.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Chloramphenicol O-Acetyltransferase,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Dexamethasone,
http://linkedlifedata.com/resource/pubmed/chemical/Glucocorticoids,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Luciferases,
http://linkedlifedata.com/resource/pubmed/chemical/Lysine,
http://linkedlifedata.com/resource/pubmed/chemical/Multienzyme Complexes,
http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Glucocorticoid
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0021-9258
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
16
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pubmed:volume |
276
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
42714-21
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:11555652-Amino Acid Motifs,
pubmed-meshheading:11555652-Animals,
pubmed-meshheading:11555652-Blotting, Western,
pubmed-meshheading:11555652-COS Cells,
pubmed-meshheading:11555652-Chloramphenicol O-Acetyltransferase,
pubmed-meshheading:11555652-Cysteine Endopeptidases,
pubmed-meshheading:11555652-Dexamethasone,
pubmed-meshheading:11555652-Down-Regulation,
pubmed-meshheading:11555652-Glucocorticoids,
pubmed-meshheading:11555652-HeLa Cells,
pubmed-meshheading:11555652-Humans,
pubmed-meshheading:11555652-Ligands,
pubmed-meshheading:11555652-Luciferases,
pubmed-meshheading:11555652-Lysine,
pubmed-meshheading:11555652-Multienzyme Complexes,
pubmed-meshheading:11555652-Mutagenesis, Site-Directed,
pubmed-meshheading:11555652-Mutation,
pubmed-meshheading:11555652-Phosphorylation,
pubmed-meshheading:11555652-Plasmids,
pubmed-meshheading:11555652-Precipitin Tests,
pubmed-meshheading:11555652-Proteasome Endopeptidase Complex,
pubmed-meshheading:11555652-Receptors, Glucocorticoid,
pubmed-meshheading:11555652-Signal Transduction,
pubmed-meshheading:11555652-Time Factors,
pubmed-meshheading:11555652-Transcription, Genetic,
pubmed-meshheading:11555652-Transcriptional Activation,
pubmed-meshheading:11555652-Transfection
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pubmed:year |
2001
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pubmed:articleTitle |
Proteasome-mediated glucocorticoid receptor degradation restricts transcriptional signaling by glucocorticoids.
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pubmed:affiliation |
Molecular Endocrinology Group, Laboratory of Signal Transduction, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
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pubmed:publicationType |
Journal Article
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