Compound A, a selective glucocorticoid receptor modulator, enhances heat shock protein Hsp70 gene promoter activation.
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 expressi...
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2013
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oai:doaj.org-article:e7db32ca698446dba6bb65b1baa9d22c2021-11-18T09:02:04ZCompound A, a selective glucocorticoid receptor modulator, enhances heat shock protein Hsp70 gene promoter activation.1932-620310.1371/journal.pone.0069115https://doaj.org/article/e7db32ca698446dba6bb65b1baa9d22c2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23935933/?tool=EBIhttps://doaj.org/toc/1932-6203Compound 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.Ilse M BeckZuzanna J DrebertRuben Hoya-AriasAli A BaharMichael DevosDorien ClarisseSofie DesmetNadia BougarneBart RuttensValerie GossyeGeertrui DeneckerSam LievensMarc BrackeJan TavernierWim DeclercqKris GevaertWim Vanden BergheGuy HaegemanKarolien De BosscherPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 7, p e69115 (2013) |
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DOAJ |
| collection |
DOAJ |
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EN |
| topic |
Medicine R Science Q |
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Medicine R Science Q Ilse M Beck Zuzanna J Drebert Ruben Hoya-Arias Ali A Bahar Michael Devos Dorien Clarisse Sofie Desmet Nadia Bougarne Bart Ruttens Valerie Gossye Geertrui Denecker Sam Lievens Marc Bracke Jan Tavernier Wim Declercq Kris Gevaert Wim Vanden Berghe Guy Haegeman Karolien De Bosscher Compound A, a selective glucocorticoid receptor modulator, enhances heat shock protein Hsp70 gene promoter activation. |
| description |
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. |
| format |
article |
| author |
Ilse M Beck Zuzanna J Drebert Ruben Hoya-Arias Ali A Bahar Michael Devos Dorien Clarisse Sofie Desmet Nadia Bougarne Bart Ruttens Valerie Gossye Geertrui Denecker Sam Lievens Marc Bracke Jan Tavernier Wim Declercq Kris Gevaert Wim Vanden Berghe Guy Haegeman Karolien De Bosscher |
| author_facet |
Ilse M Beck Zuzanna J Drebert Ruben Hoya-Arias Ali A Bahar Michael Devos Dorien Clarisse Sofie Desmet Nadia Bougarne Bart Ruttens Valerie Gossye Geertrui Denecker Sam Lievens Marc Bracke Jan Tavernier Wim Declercq Kris Gevaert Wim Vanden Berghe Guy Haegeman Karolien De Bosscher |
| author_sort |
Ilse M Beck |
| title |
Compound A, a selective glucocorticoid receptor modulator, enhances heat shock protein Hsp70 gene promoter activation. |
| title_short |
Compound A, a selective glucocorticoid receptor modulator, enhances heat shock protein Hsp70 gene promoter activation. |
| title_full |
Compound A, a selective glucocorticoid receptor modulator, enhances heat shock protein Hsp70 gene promoter activation. |
| title_fullStr |
Compound A, a selective glucocorticoid receptor modulator, enhances heat shock protein Hsp70 gene promoter activation. |
| title_full_unstemmed |
Compound A, a selective glucocorticoid receptor modulator, enhances heat shock protein Hsp70 gene promoter activation. |
| title_sort |
compound a, a selective glucocorticoid receptor modulator, enhances heat shock protein hsp70 gene promoter activation. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/e7db32ca698446dba6bb65b1baa9d22c |
| work_keys_str_mv |
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