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Functional modulation of the glucocorticoid receptor and suppression of NF-kappaB-dependent transcription by ursodeoxycholic acid.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2001 Dec 14; Vol. 276 (50), pp. 47371-8. Date of Electronic Publication: 2001 Sep 27. - Publication Year :
- 2001
-
Abstract
- Ursodeoxycholic acid (UDCA) is the current mainstay of treatment for various liver diseases including primary biliary cirrhosis. UDCA acts as a bile secretagogue, cytoprotective agent, immunomodulator, and inhibitor of cellular apoptosis. Despite this cumulative evidence of the cytoprotective and immunosuppressive effects of UDCA, both the target molecule and pathway of UDCA action remain unknown. We previously described that, in the absence of glucocorticoid ligand, UDCA activates the glucocorticoid receptor (GR) into DNA binding species but does not elicit its transactivational function in a transient transfection assay. Here we further studied the molecular mechanism of UDCA action and revealed that the ligand binding domain of the GR is responsible for UDCA-dependent nuclear translocation of the GR. Indeed, we demonstrated that UDCA acts on the distinct region of the ligand binding domain when compared with the classical GR agonist dexamethasone, resulting in loss of coactivator recruitment and differential regulation of gene expression by the GR. Our data clearly indicated that UDCA, at least in part via activation of the GR, suppresses NF-kappaB-dependent transcription through the intervention of GR-p65 interaction. Together with the established clinical safety of UDCA, we may propose that UDCA could be a prototypical compound for development of a novel and selective GR modifier.
- Subjects :
- Active Transport, Cell Nucleus
Administration, Topical
Animals
Anti-Inflammatory Agents pharmacology
Blotting, Western
COS Cells
Cholagogues and Choleretics metabolism
DNA metabolism
DNA Mutational Analysis
Dexamethasone pharmacology
Gene Expression Regulation
Genes, Reporter
Glucocorticoids
Green Fluorescent Proteins
HeLa Cells
Humans
Immunohistochemistry
Ligands
Luminescent Proteins metabolism
Plasmids metabolism
Precipitin Tests
Protein Binding
Protein Structure, Tertiary
Protein Transport
Recombinant Fusion Proteins metabolism
Signal Transduction
Time Factors
Transcription Factor RelA
Transcriptional Activation
Transfection
NF-kappa B metabolism
Receptors, Glucocorticoid metabolism
Transcription, Genetic
Ursodeoxycholic Acid metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 276
- Issue :
- 50
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 11577102
- Full Text :
- https://doi.org/10.1074/jbc.M107098200