期刊
NUCLEIC ACIDS RESEARCH
卷 41, 期 1, 页码 90-109出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gks916
关键词
-
资金
- Deutsche Forschungsgemeinschaft (DFG) [Kr1143/5-3, Kr1143/7-1, SFB566/Z02, TRR81/B2]
- Deutscher akademischer Austauschdienst [A/08/98404]
- Excellence Cluster Cardio-Pulmonary System (ECCPS)
- LOEWE/UGMLC program
- NIH [R01 DK073639]
- CCFA [SRA 2737]
- DFG
- [SCHM 1417/4-2]
- [SCHM 1417/7-1]
- [SCHM 1417/8-1]
- [GRK 1566/1]
- [SFB/TRR81]
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-kappa B p65 and its deacetylation at various lysines. NF-kappa 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-kappa 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据