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

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 G...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	S. J. Desmet, N. Bougarne, L. Van Moortel, L. De Cauwer, J. Thommis, M. Vuylsteke, D. Ratman, R. Houtman, J. Tavernier, K. De Bosscher
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ae5e8eb524af4a239064508dc35c8b0a
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ae5e8eb524af4a239064508dc35c8b0a
record_format	dspace
spelling	oai:doaj.org-article:ae5e8eb524af4a239064508dc35c8b0a2021-12-02T12:31:46ZCompound A influences gene regulation of the Dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment10.1038/s41598-017-07941-y2045-2322https://doaj.org/article/ae5e8eb524af4a239064508dc35c8b0a2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07941-yhttps://doaj.org/toc/2045-2322Abstract 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.S. J. DesmetN. BougarneL. Van MoortelL. De CauwerJ. ThommisM. VuylstekeD. RatmanR. HoutmanJ. TavernierK. De BosscherNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q S. J. Desmet N. Bougarne L. Van Moortel L. De Cauwer J. Thommis M. Vuylsteke D. Ratman R. Houtman J. Tavernier K. De Bosscher Compound A influences gene regulation of the Dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment
description	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.
format	article
author	S. J. Desmet N. Bougarne L. Van Moortel L. De Cauwer J. Thommis M. Vuylsteke D. Ratman R. Houtman J. Tavernier K. De Bosscher
author_facet	S. J. Desmet N. Bougarne L. Van Moortel L. De Cauwer J. Thommis M. Vuylsteke D. Ratman R. Houtman J. Tavernier K. De Bosscher
author_sort	S. J. Desmet
title	Compound A influences gene regulation of the Dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment
title_short	Compound A influences gene regulation of the Dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment
title_full	Compound A influences gene regulation of the Dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment
title_fullStr	Compound A influences gene regulation of the Dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment
title_full_unstemmed	Compound A influences gene regulation of the Dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment
title_sort	compound a influences gene regulation of the dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ae5e8eb524af4a239064508dc35c8b0a
work_keys_str_mv	AT sjdesmet compoundainfluencesgeneregulationofthedexamethasoneactivatedglucocorticoidreceptorbyalternativecofactorrecruitment AT nbougarne compoundainfluencesgeneregulationofthedexamethasoneactivatedglucocorticoidreceptorbyalternativecofactorrecruitment AT lvanmoortel compoundainfluencesgeneregulationofthedexamethasoneactivatedglucocorticoidreceptorbyalternativecofactorrecruitment AT ldecauwer compoundainfluencesgeneregulationofthedexamethasoneactivatedglucocorticoidreceptorbyalternativecofactorrecruitment AT jthommis compoundainfluencesgeneregulationofthedexamethasoneactivatedglucocorticoidreceptorbyalternativecofactorrecruitment AT mvuylsteke compoundainfluencesgeneregulationofthedexamethasoneactivatedglucocorticoidreceptorbyalternativecofactorrecruitment AT dratman compoundainfluencesgeneregulationofthedexamethasoneactivatedglucocorticoidreceptorbyalternativecofactorrecruitment AT rhoutman compoundainfluencesgeneregulationofthedexamethasoneactivatedglucocorticoidreceptorbyalternativecofactorrecruitment AT jtavernier compoundainfluencesgeneregulationofthedexamethasoneactivatedglucocorticoidreceptorbyalternativecofactorrecruitment AT kdebosscher compoundainfluencesgeneregulationofthedexamethasoneactivatedglucocorticoidreceptorbyalternativecofactorrecruitment
_version_	1718394299208433664

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

Ejemplares similares