Linked Life Data

10488132

Source:http://linkedlifedata.com/resource/pubmed/id/10488132

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
39
pubmed:dateCreated
1999-11-4
pubmed:abstractText
Alternative splicing of the human glucocorticoid receptor gene generates a nonhormone binding splice variant (hGRbeta) that differs from the wild-type receptor (hGRalpha) only at the carboxyl terminus. Previously we have shown that hGRbeta inhibits the transcriptional activity of hGRalpha, which is consistent with reports of elevated hGRbeta expression in patients with generalized and tissue-specific glucocorticoid resistance. The potential role of hGRbeta in the regulation of target cell sensitivity to glucocorticoids prompted us to further evaluate its dominant negative activity in other model systems and to investigate its mode of action. We demonstrate in multiple cell types that hGRbeta inhibits hGRalpha-mediated activation of the mouse mammary tumor virus promoter. In contrast, the ability of the progesterone and androgen receptors to activate this promoter is only weakly affected by hGRbeta. hGRbeta also inhibits hGRalpha-mediated repression of an NF-kappaB-responsive promoter but does not interfere with homologous down-regulation of hGRalpha. We show that hGRbeta can associate with the heat shock protein hsp90 although with lower affinity than hGRalpha. In addition, hGRbeta binds GRE-containing DNA with a greater capacity than hGRalpha in the absence of glucocorticoids. Glucocorticoid treatment enhances hGRalpha, but not hGRbeta, binding to DNA. Moreover, we demonstrate that hGRalpha and hGRbeta can physically associate with each other in a heterodimer. Finally, we show that the dominant negative activity of hGRbeta resides within its unique carboxyl-terminal 15 amino acids. Taken together, our results suggest that formation of transcriptionally impaired hGRalpha-hGRbeta heterodimers is an important component of the mechanism responsible for the dominant negative activity of hGRbeta.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
24
pubmed:volume
274
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
27857-66
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:10488132-Alternative Splicing, pubmed-meshheading:10488132-Animals, pubmed-meshheading:10488132-COS Cells, pubmed-meshheading:10488132-Cell Line, pubmed-meshheading:10488132-Chloramphenicol O-Acetyltransferase, pubmed-meshheading:10488132-Dexamethasone, pubmed-meshheading:10488132-Dimerization, pubmed-meshheading:10488132-Gene Expression Regulation, pubmed-meshheading:10488132-Genes, Reporter, pubmed-meshheading:10488132-Humans, pubmed-meshheading:10488132-Luciferases, pubmed-meshheading:10488132-Mice, pubmed-meshheading:10488132-NF-kappa B, pubmed-meshheading:10488132-Progesterone, pubmed-meshheading:10488132-Promoter Regions, Genetic, pubmed-meshheading:10488132-Protein Isoforms, pubmed-meshheading:10488132-Receptors, Glucocorticoid, pubmed-meshheading:10488132-Recombinant Fusion Proteins, pubmed-meshheading:10488132-Recombinant Proteins, pubmed-meshheading:10488132-Transcription, Genetic, pubmed-meshheading:10488132-Transfection
pubmed:year
1999
pubmed:articleTitle
The dominant negative activity of the human glucocorticoid receptor beta isoform. Specificity and mechanisms of action.
pubmed:affiliation
Laboratory of Signal Transduction, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S.