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Compound A influences gene regulation of the dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment

Sofie Desmet UGent, Nadia Bougarne UGent, Laura Van Moortel UGent, Lode De Cauwer, Jonathan Thommis UGent, M Vuylsteke, Dariusz Ratman, R Houtman, Jan Tavernier UGent and Karolien De Bosscher UGent (2017) SCIENTIFIC REPORTS. 7.
abstract
The glucocorticoid receptor (GR) is a transcription factor of which the underlying gene regulatory mechanisms are complex and incompletely understood. The non-steroidal anti-inflammatory Compound A (CpdA), a selective GR modulating compound in various cell models, has been shown to favour GR-mediated gene repression but not GR-mediated gene activation. Shifting balances towards only a particular subset of GR gene regulatory events may be of benefit in the treatment of inflammatory diseases. We present evidence to support that the combination of CpdA with Dexamethasone (DEX), a classic steroidal GR ligand, can shape GR function towards a unique gene regulatory profile in a cell type-dependent manner. The molecular basis hereof is a changed GR phosphorylation status concomitant with a change in the GR cofactor recruitment profile. We subsequently identified and confirmed the orphan nuclear receptor SHP as a coregulator that is specifically enriched at GR when CpdA and DEX are combined. Combining CpdA with DEX not only leads to stronger suppression of pro-inflammatory gene expression, but also enhanced anti-inflammatory GR target gene expression in epithelial cells, making ligand combination strategies in future a potentially attractive alternative manner of skewing and fine-tuning GR effects towards an improved therapeutic benefit.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
FACTOR-KAPPA-B, COLLAGEN-INDUCED ARTHRITIS, SYNOVIAL FIBROBLASTS, MODULATOR COMPOUND, LEPTIN RECEPTOR, PLANT-ORIGIN, IN-VIVO, INFLAMMATION, TRANSACTIVATION, MECHANISMS
journal title
SCIENTIFIC REPORTS
Sci. Rep.
volume
7
article number
8063
pages
14 pages
Web of Science type
Article
Web of Science id
000407559800030
ISSN
2045-2322
DOI
10.1038/s41598-017-07941-y
language
English
UGent publication?
yes
classification
U
copyright statement
I don't know the status of the copyright for this publication
id
8529315
handle
http://hdl.handle.net/1854/LU-8529315
date created
2017-08-22 08:12:27
date last changed
2017-10-16 07:26:36
@article{8529315,
  abstract     = {The glucocorticoid receptor (GR) is a transcription factor of which the underlying gene regulatory mechanisms are complex and incompletely understood. The non-steroidal anti-inflammatory Compound A (CpdA), a selective GR modulating compound in various cell models, has been shown to favour GR-mediated gene repression but not GR-mediated gene activation. Shifting balances towards only a particular subset of GR gene regulatory events may be of benefit in the treatment of inflammatory diseases. We present evidence to support that the combination of CpdA with Dexamethasone (DEX), a classic steroidal GR ligand, can shape GR function towards a unique gene regulatory profile in a cell type-dependent manner. The molecular basis hereof is a changed GR phosphorylation status concomitant with a change in the GR cofactor recruitment profile. We subsequently identified and confirmed the orphan nuclear receptor SHP as a coregulator that is specifically enriched at GR when CpdA and DEX are combined. Combining CpdA with DEX not only leads to stronger suppression of pro-inflammatory gene expression, but also enhanced anti-inflammatory GR target gene expression in epithelial cells, making ligand combination strategies in future a potentially attractive alternative manner of skewing and fine-tuning GR effects towards an improved therapeutic benefit.},
  articleno    = {8063},
  author       = {Desmet, Sofie and Bougarne, Nadia and Van Moortel, Laura and De Cauwer, Lode and Thommis, Jonathan and Vuylsteke, M and Ratman, Dariusz and Houtman, R and Tavernier, Jan and De Bosscher, Karolien},
  issn         = {2045-2322},
  journal      = {SCIENTIFIC REPORTS},
  keyword      = {FACTOR-KAPPA-B,COLLAGEN-INDUCED ARTHRITIS,SYNOVIAL FIBROBLASTS,MODULATOR COMPOUND,LEPTIN RECEPTOR,PLANT-ORIGIN,IN-VIVO,INFLAMMATION,TRANSACTIVATION,MECHANISMS},
  language     = {eng},
  pages        = {14},
  title        = {Compound A influences gene regulation of the dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment},
  url          = {http://dx.doi.org/10.1038/s41598-017-07941-y},
  volume       = {7},
  year         = {2017},
}

Chicago
Desmet, Sofie, Nadia Bougarne, Laura Van Moortel, Lode De Cauwer, Jonathan Thommis, M Vuylsteke, Dariusz Ratman, R Houtman, Jan Tavernier, and Karolien De Bosscher. 2017. “Compound A Influences Gene Regulation of the Dexamethasone-activated Glucocorticoid Receptor by Alternative Cofactor Recruitment.” Scientific Reports 7.
APA
Desmet, Sofie, Bougarne, N., Van Moortel, L., De Cauwer, L., Thommis, J., Vuylsteke, M., Ratman, D., et al. (2017). Compound A influences gene regulation of the dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment. SCIENTIFIC REPORTS, 7.
Vancouver
1.
Desmet S, Bougarne N, Van Moortel L, De Cauwer L, Thommis J, Vuylsteke M, et al. Compound A influences gene regulation of the dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment. SCIENTIFIC REPORTS. 2017;7.
MLA
Desmet, Sofie, Nadia Bougarne, Laura Van Moortel, et al. “Compound A Influences Gene Regulation of the Dexamethasone-activated Glucocorticoid Receptor by Alternative Cofactor Recruitment.” SCIENTIFIC REPORTS 7 (2017): n. pag. Print.