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The nature of the GRE influences the screening for GR-activity enhancing modulators

Karen Dendoncker (UGent) , Steven Timmermans (UGent) , Kelly Van Looveren (UGent) , Lode De Cauwer (UGent) , Karolien De Bosscher (UGent) and Claude Libert (UGent)
(2017) PLOS ONE. 12(7).
Author
Organization
Abstract
Glucocorticoid resistance (GCR), i.e. unresponsiveness to the beneficial anti-inflammatory activities of the glucocorticoid receptor (GR), poses a serious problem in the treatment of inflammatory diseases. One possible solution to try and overcome GCR, is to identify molecules that prevent or revert GCR by hyper-stimulating the biological activity of the GR. To this purpose, we screened for compounds that potentiate the dexamethasone (Dex)induced transcriptional activity of GR. To monitor GR transcriptional activity, the screen was performed using the lung epithelial cell line A549 in which a glucocorticoid responsive element (GRE) coupled to a luciferase reporter gene construct was stably integrated. Histone deacetylase inhibitors (HDACi) such as Vorinostat and Belinostat are two broad-spectrum HDACi that strongly increased the Dex-induced luciferase expression in our screening system. In sharp contrast herewith, results from a genome-wide transcriptome analysis of Dexinduced transcripts using RNAseq, revealed that Belinostat impairs the ability of GR to transactivate target genes. The stimulatory effect of Belinostat in the luciferase screen further depends on the nature of the reporter construct. In conclusion, a profound discrepancy was observed between HDACi effects on two different synthetic promoter-luciferase reporter systems. The favorable effect of HDACi on gene expression should be evaluated with care, when considering them as potential therapeutic agents. GEO accession number GSE96649.
Keywords
HISTONE DEACETYLASE INHIBITORS, NF-KAPPA-B, GLUCOCORTICOID-RECEPTOR, AGONIST, HUMAN OCULAR CELLS, INFLAMMATORY DISEASES, DOWN-REGULATION, CLASS-I, TRANSCRIPTION, ACETYLATION, COMPLEXES

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Citation

Please use this url to cite or link to this publication:

MLA
Dendoncker, Karen et al. “The Nature of the GRE Influences the Screening for GR-activity Enhancing Modulators.” PLOS ONE 12.7 (2017): n. pag. Print.
APA
Dendoncker, K., Timmermans, S., Van Looveren, K., De Cauwer, L., De Bosscher, K., & Libert, C. (2017). The nature of the GRE influences the screening for GR-activity enhancing modulators. PLOS ONE, 12(7).
Chicago author-date
Dendoncker, Karen, Steven Timmermans, Kelly Van Looveren, Lode De Cauwer, Karolien De Bosscher, and Claude Libert. 2017. “The Nature of the GRE Influences the Screening for GR-activity Enhancing Modulators.” Plos One 12 (7).
Chicago author-date (all authors)
Dendoncker, Karen, Steven Timmermans, Kelly Van Looveren, Lode De Cauwer, Karolien De Bosscher, and Claude Libert. 2017. “The Nature of the GRE Influences the Screening for GR-activity Enhancing Modulators.” Plos One 12 (7).
Vancouver
1.
Dendoncker K, Timmermans S, Van Looveren K, De Cauwer L, De Bosscher K, Libert C. The nature of the GRE influences the screening for GR-activity enhancing modulators. PLOS ONE. 2017;12(7).
IEEE
[1]
K. Dendoncker, S. Timmermans, K. Van Looveren, L. De Cauwer, K. De Bosscher, and C. Libert, “The nature of the GRE influences the screening for GR-activity enhancing modulators,” PLOS ONE, vol. 12, no. 7, 2017.
@article{8529448,
  abstract     = {Glucocorticoid resistance (GCR), i.e. unresponsiveness to the beneficial anti-inflammatory activities of the glucocorticoid receptor (GR), poses a serious problem in the treatment of inflammatory diseases. One possible solution to try and overcome GCR, is to identify molecules that prevent or revert GCR by hyper-stimulating the biological activity of the GR. To this purpose, we screened for compounds that potentiate the dexamethasone (Dex)induced transcriptional activity of GR. To monitor GR transcriptional activity, the screen was performed using the lung epithelial cell line A549 in which a glucocorticoid responsive element (GRE) coupled to a luciferase reporter gene construct was stably integrated. Histone deacetylase inhibitors (HDACi) such as Vorinostat and Belinostat are two broad-spectrum HDACi that strongly increased the Dex-induced luciferase expression in our screening system. In sharp contrast herewith, results from a genome-wide transcriptome analysis of Dexinduced transcripts using RNAseq, revealed that Belinostat impairs the ability of GR to transactivate target genes. The stimulatory effect of Belinostat in the luciferase screen further depends on the nature of the reporter construct. In conclusion, a profound discrepancy was observed between HDACi effects on two different synthetic promoter-luciferase reporter systems. The favorable effect of HDACi on gene expression should be evaluated with care, when considering them as potential therapeutic agents. GEO accession number GSE96649.},
  articleno    = {e0181101},
  author       = {Dendoncker, Karen and Timmermans, Steven and Van Looveren, Kelly and De Cauwer, Lode and De Bosscher, Karolien and Libert, Claude},
  issn         = {1932-6203},
  journal      = {PLOS ONE},
  keywords     = {HISTONE DEACETYLASE INHIBITORS,NF-KAPPA-B,GLUCOCORTICOID-RECEPTOR,AGONIST,HUMAN OCULAR CELLS,INFLAMMATORY DISEASES,DOWN-REGULATION,CLASS-I,TRANSCRIPTION,ACETYLATION,COMPLEXES},
  language     = {eng},
  number       = {7},
  pages        = {17},
  title        = {The nature of the GRE influences the screening for GR-activity enhancing modulators},
  url          = {http://dx.doi.org/10.1371/journal.pone.0181101},
  volume       = {12},
  year         = {2017},
}

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