Compound A, a Selective Glucocorticoid Receptor Modulator, Enhances Heat Shock Protein Hsp70 Gene Promoter Activation Journal Article
| Authors: | Beck, I. M.; Drebert, Z. J.; Hoya-Arias, R.; Bahar, A. A.; Devos, M.; Clarisse, D.; Desmet, S.; Bougarne, N.; Ruttens, B.; Gossye, V.; Denecker, G.; Lievens, S.; Bracke, M.; Tavernier, J.; Declercq, W.; Gevaert, K.; Van Berghe, W.; Haegeman, G.; De Bosscher, K. |
| Article Title: | Compound A, a Selective Glucocorticoid Receptor Modulator, Enhances Heat Shock Protein Hsp70 Gene Promoter Activation |
| Abstract: | Compound A possesses glucocorticoid receptor (GR)-dependent anti-inflammatory properties. Just like classical GR ligands, Compound A can repress NF-κB-mediated gene expression. However, the monomeric Compound A-activated GR is unable to trigger glucocorticoid response element-regulated gene expression. The heat shock response potently activates heat shock factor 1 (HSF1), upregulates Hsp70, a known GR chaperone, and also modulates various aspects of inflammation. We found that the selective GR modulator Compound A and heat shock trigger similar cellular effects in A549 lung epithelial cells. With regard to their anti-inflammatory mechanism, heat shock and Compound A are both able to reduce TNF-stimulated IκBα degradation and NF-κB p65 nuclear translocation. We established an interaction between Compound A-activated GR and Hsp70, but remarkably, although the presence of the Hsp70 chaperone as such appears pivotal for the Compound A-mediated inflammatory gene repression, subsequent novel Hsp70 protein synthesis is uncoupled from an observed CpdA-induced Hsp70 mRNA upregulation and hence obsolete in mediating CpdA's anti-inflammatory effect. The lack of a Compound A-induced increase in Hsp70 protein levels in A549 cells is not mediated by a rapid proteasomal degradation of Hsp70 or by a Compound A-induced general block on translation. Similar to heat shock, Compound A can upregulate transcription of Hsp70 genes in various cell lines and BALB/c mice. Interestingly, whereas Compound A-dependent Hsp70 promoter activation is GR-dependent but HSF1-independent, heat shock-induced Hsp70 expression alternatively occurs in a GR-independent and HSF1-dependent manner in A549 lung epithelial cells. © 2013 Beck et al. |
| Keywords: | controlled study; unclassified drug; human cell; promoter region; nonhuman; animal cell; mouse; gene; gene expression; protein degradation; intracellular transport; immunoglobulin enhancer binding protein; transcription factor rela; transcription regulation; messenger rna; protein synthesis; gene repression; epithelium cell; rna translation; upregulation; antiinflammatory activity; heat shock protein 70; heat shock response; heat shock transcription factor 1; tumor necrosis factor; lung alveolus epithelium; compound a; glucocorticoid receptor stimulating agent; hormone receptor stimulating agent; hsp70 gene |
| Journal Title: | PLoS ONE |
| Volume: | 8 |
| Issue: | 7 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Date Published: | 2013-07-30 |
| Start Page: | e69115 |
| Language: | English |
| DOI: | 10.1371/journal.pone.0069115 |
| PROVIDER: | scopus |
| PMCID: | PMC3728325 |
| PUBMED: | 23935933 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 September 2013" - "CODEN: POLNC" - "Source: Scopus" |
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