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

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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.
Keywords
FACTOR-KAPPA-B, COLLAGEN-INDUCED ARTHRITIS, SYNOVIAL FIBROBLASTS, MODULATOR COMPOUND, LEPTIN RECEPTOR, PLANT-ORIGIN, IN-VIVO, INFLAMMATION, TRANSACTIVATION, MECHANISMS

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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.
@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},
}

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