Source:http://linkedlifedata.com/resource/pubmed/id/15736964
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions |
umls-concept:C0017262,
umls-concept:C0017710,
umls-concept:C0035820,
umls-concept:C0185117,
umls-concept:C0243192,
umls-concept:C0441655,
umls-concept:C0542341,
umls-concept:C0728938,
umls-concept:C1148673,
umls-concept:C1334867,
umls-concept:C1425727,
umls-concept:C1704241,
umls-concept:C1879547,
umls-concept:C2911684
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| pubmed:issue |
9
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| pubmed:dateCreated |
2005-3-1
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| pubmed:abstractText |
The determinants of the partial agonist activity of most antisteroids complexed with steroid receptors are not well understood. We now examine the role of the N-terminal half of the glucocorticoid receptor (GR) including the activation domain (AF-1), the DNA binding site sequence, receptor contact with DNA, and coactivator binding on the expression of partial agonist activity in two cell lines for GRs bound by five antiglucocorticoids: dexamethasone mesylate (Dex-Mes), dexamethasone oxetanone (Dex-Ox), progesterone (Prog), deoxycorticosterone (DOC), and RU486. Using truncated GRs, we find that the N-terminal half of GR and the AF-1 domain are dispensable for the partial agonist activity of antiglucocorticoids. This contrasts with the AF-1 domain being required for the partial agonist activity of antisteroids with most steroid receptors. DNA sequence (MMTV vs a simple GRE enhancer) and cell-specific factors (CV-1 vs Cos-7) exert minor effects on the level of partial agonist activity. Small activity differences for some complexes of GAL4/GR chimeras with GR- vs GAL-responsive reporters suggest a contribution of DNA-induced conformational changes. A role for steroid-regulated coactivator binding to GRs is compatible with the progressively smaller increase in partial agonist activity of Dex-Mes > Prog > RU486 with added GRIP1 in CV-1 cells. This hypothesis is consistent with titration experiments, where low concentrations of GRIP1 more effectively increase the partial agonist activity of Dex-Mes than Prog complexes. Furthermore, ligand-dependent GRIP1 binding to DNA-bound GR complexes decreases in the order of Dex > Dex-Mes > Prog > RU486. Thus, the partial agonist activity of a given GR-steroid complex in CV-1 cells correlates with its cell-free binding of GRIP1. The ability to modify the levels of partial agonist activity through changes in steroid structure, DNA sequence, specific DNA-induced conformational changes, and coactivator binding suggests that useful variations in endocrine therapies may be possible by the judicious selection of these parameters to afford gene and tissue selective results.
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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/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Desoxycorticosterone,
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/Mifepristone,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Receptor Coactivator 2,
http://linkedlifedata.com/resource/pubmed/chemical/Peptide Fragments,
http://linkedlifedata.com/resource/pubmed/chemical/Progesterone,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Glucocorticoid,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/dexamethasone 21-methanesulfonate,
http://linkedlifedata.com/resource/pubmed/chemical/dexamethasone oxetanone
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| pubmed:status |
MEDLINE
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| pubmed:month |
Mar
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| pubmed:issn |
0006-2960
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
8
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| pubmed:volume |
44
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
3547-61
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| pubmed:dateRevised |
2005-11-17
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| pubmed:meshHeading |
pubmed-meshheading:15736964-Animals,
pubmed-meshheading:15736964-Binding Sites,
pubmed-meshheading:15736964-COS Cells,
pubmed-meshheading:15736964-Cercopithecus aethiops,
pubmed-meshheading:15736964-DNA-Binding Proteins,
pubmed-meshheading:15736964-Desoxycorticosterone,
pubmed-meshheading:15736964-Dexamethasone,
pubmed-meshheading:15736964-Gene Expression Regulation,
pubmed-meshheading:15736964-Glucocorticoids,
pubmed-meshheading:15736964-Ligands,
pubmed-meshheading:15736964-Mifepristone,
pubmed-meshheading:15736964-Nuclear Receptor Coactivator 2,
pubmed-meshheading:15736964-Peptide Fragments,
pubmed-meshheading:15736964-Progesterone,
pubmed-meshheading:15736964-Protein Structure, Tertiary,
pubmed-meshheading:15736964-Receptors, Glucocorticoid,
pubmed-meshheading:15736964-Response Elements,
pubmed-meshheading:15736964-Trans-Activators,
pubmed-meshheading:15736964-Transcription Factors,
pubmed-meshheading:15736964-Up-Regulation
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| pubmed:year |
2005
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| pubmed:articleTitle |
Role of activation function domain-1, DNA binding, and coactivator GRIP1 in the expression of partial agonist activity of glucocorticoid receptor-antagonist complexes.
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| pubmed:affiliation |
Steroid Hormones Section, NIDDK/LMCB, National Institutes of Health, Bethesda, Maryland 20892, USA.
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| pubmed:publicationType |
Journal Article
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