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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
46
pubmed:dateCreated
2001-11-12
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
16
pubmed:volume
276
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
42714-21
pubmed:dateRevised
2008-11-21
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
pubmed:year
2001
pubmed:articleTitle
Proteasome-mediated glucocorticoid receptor degradation restricts transcriptional signaling by glucocorticoids.
pubmed:affiliation
Molecular Endocrinology Group, Laboratory of Signal Transduction, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
pubmed:publicationType
Journal Article