期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 71, 期 1, 页码 143-163出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-013-1367-4
关键词
Glucocorticoids; Inflammation; Mitogen-activated protein kinase (MAPK); Selective GR modulator; c-Jun; Jun N-terminal kinase (JNK)
资金
- Geconcerteerde Onderzoeksactiviteiten (GOA) grant from UGent
- IWT-Vlaanderen
- Televie Luxembourg
- Fondation de Recherche Cancer et Sang
- Recherches Scientifiques Luxembourg association
- Een Haerz fir kriibskrank Kanner association
- Action Lions Vaincre le Cancer association
- European Union [215009]
- Foundation for Scientific Cooperation between Germany and Luxemburg
- Deutsche Forschungsgemeinschaft (DFG) [JA1741/2-1]
- National Research Foundation (NRF)
- MEST of Korea for Tumor Microenvironment Global Core Research Center (GCRC) grant [2012-0001184]
- Seoul National University Research grant
- Research Settlement Fund for the new faculty of SNU
Glucocorticoids (GCs) block inflammation via interference of the liganded glucocorticoid receptor (GR) with the activity of pro-inflammatory transcription factors NF-kappa B 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-kappa B- 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.
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