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The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-kappaB

Ziesché, Elisabeth ; Kettner-Buhrow, Daniela ; Weber, Axel ; Wittwer, Tobias ; Jurida, Liane ; Soelch, Johanna ; Müller, Helmut ; Newel, Doris ; Kronich, Petra ; Schneider, Heike ; Dittrich-Breiholz, Oliver ; Bhaskara, Srividya ; Hiebert, Scott W. ; Hottiger, Michael O. ; Li, Haiying ; Burstein, Ezra ; Schmitz, M. Lienhard ; Kracht, Michael

Originalveröffentlichung: (2012) Nucleic Acids Research, 1-20; doi:10.1093/nar/gks916
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URN: urn:nbn:de:hebis:26-opus-90755

Freie Schlagwörter (Englisch): histone deacetylase 3 (HDAC3) , NF-kappaB p65 , positive gen-regulation of IL-1 , co-activator in inflammatory signaling pathways
Sammlung: Open Access - Publikationsfonds
Universität Justus-Liebig-Universität Gießen
Institut: Rudolf-Buchheim-Institute of Pharmacology
Fachgebiet: Medizin
DDC-Sachgruppe: Medizin
Dokumentart: Aufsatz
Sprache: Englisch
Erstellungsjahr: 2012
Publikationsdatum: 20.11.2012
Kurzfassung auf Englisch: Histone deacetylase (HDAC) 3, as a cofactor in co-repressor complexes containing silencing mediator for retinoid or thyroid-hormone receptors (SMRT) and nuclear receptor co-repressor (N-CoR), has been shown to repress gene transcription in a variety of contexts. Here, we reveal a novel role for HDAC3 as a positive regulator of IL-1-induced gene expression. Various experimental approaches involving RNAi-mediated knockdown, conditional gene deletion or small molecule inhibitors indicate a positive role of HDAC3 for transcription of the majority of IL-1-induced human or murine genes. This effect was independent from the gene regulatory effects mediated by the broad-spectrum HDAC inhibitor trichostatin A (TSA) and thus suggests IL-1-specific functions for HDAC3. The stimulatory function of HDAC3 for inflammatory gene expression involves a mechanism that uses binding to NF-?B p65 and its deacetylation at various lysines. NF-?B p65-deficient cells stably reconstituted to express acetylation mimicking forms of p65 (p65 K/Q) had largely lost their potential to stimulate IL-1-triggered gene expression, implying that the co-activating property of HDAC3 involves the removal of inhibitory NF-?B p65 acetylations at K122, 123, 314 and 315. These data describe a novel function for HDAC3 as a co-activator in inflammatory signaling pathways and help to explain the anti-inflammatory effects frequently observed for HDAC inhibitors in (pre)clinical use.
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