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  • Selective modulation of the glucocorticoid receptor can distinguish between transrepression of NF-κB and AP-1.

Selective modulation of the glucocorticoid receptor can distinguish between transrepression of NF-κB and AP-1.

Cellular and molecular life sciences : CMLS (2013-06-21)
Karolien De Bosscher, Ilse M Beck, Lien Dejager, Nadia Bougarne, Anthoula Gaigneaux, Sébastien Chateauvieux, Dariusz Ratman, Marc Bracke, Jan Tavernier, Wim Vanden Berghe, Claude Libert, Marc Diederich, Guy Haegeman
ABSTRACT

Glucocorticoids (GCs) block inflammation via interference of the liganded glucocorticoid receptor (GR) with the activity of pro-inflammatory transcription factors NF-κB and AP-1, a mechanism known as transrepression. This mechanism is believed to involve the activity of GR monomers. Here, we explored how the GR monomer-favoring Compound A (CpdA) affects AP-1 activation and activity. Our results demonstrate that non-steroidal CpdA, unlike classic steroidal GCs, blocks NF-κB- but not AP-1-driven gene expression. CpdA rather sustains AP-1-driven gene expression, a result which could mechanistically be explained by the failure of CpdA to block upstream JNK kinase activation and concomitantly also phosphorylation of c-Jun. In concordance and in contrast to DEX, CpdA maintained the expression of the activated AP-1 target gene c-jun, as well as the production of the c-Jun protein. As for the underlying mechanism, GR is a necessary intermediate in the CpdA-mediated gene expression of AP-1-regulated genes, but seems to be superfluous to CpdA-mediated JNK phosphorylation prolongation. The latter phenomenon concurs with the inability of CpdA to stimulate DUSP1 gene expression. ChIP analysis demonstrates that DEX-activated GR, but not CpdA-activated GR, is recruited to AP-1-driven promoters. Furthermore, in mice we observed that CpdA instigates a strong enhancement of TNF-induced AP-1-driven gene expression. Finally, we demonstrate that this phenomenon coincides with an increased sensitivity towards TNF lethality, and implicate again a role for JNK2. In conclusion, our data support the hypothesis that a ligand-induced differential conformation of GR yields a different transcription factor cross-talk profile.

MATERIALS
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Brand
Product Description

Sigma-Aldrich
Staurosporine from Streptomyces sp., ≥98% (HPLC), film
Supelco
Staurosporine, VETRANAL®, analytical standard
Sigma-Aldrich
Staurosporine from Streptomyces sp., for molecular biology, ≥95% (HPLC)