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 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.
Laboratory of Experimental Cancer Research (LECR), Department of Radiation Therapy & Experimental Cancer Research, Ghent University, Ghent, Belgium. Ilse.Beck@Ugent.be
Ilse M
IM
Beck
Zuzanna J
ZJ
Drebert
Ruben
R
Hoya-Arias
Ali A
AA
Bahar
Michael
M
Devos
Dorien
D
Clarisse
Sofie
S
Desmet
Nadia
N
Bougarne
Bart
B
Ruttens
Valerie
V
Gossye
Geertrui
G
Denecker
Sam
S
Lievens
Marc
M
Bracke
Jan
J
Tavernier
Wim
W
Declercq
Kris
K
Gevaert
Wim
W
Vanden Berghe
Guy
G
Haegeman
Karolien
K
De Bosscher
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006801:Humans; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000378:metabolism*; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors