Crucial Roles of Binding Sites for Nf-kappab and C/Ebps in Ikappab-zeta-mediated Transcriptional Activation.
From: Department of Molecular and Cellular Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
The Biochemical journal
- Publish Date: Aug 2007
- ISSN: 1470-8728
- Volume: 405
- Issue: 3
- Pages: 605-15
- Medium: Internet
- Language: English
- Citation (JAMA): Matsuo Susumu, Yamazaki Soh, Takeshige Koichiro, et al. Crucial Roles of Binding Sites for Nf-kappab and C/Ebps in Ikappab-zeta-mediated Transcriptional Activation.. Biochem. J. Aug 2007;405:605-15
Abstract
IkappaB-zeta [inhibitor of NF-kappaB (nuclear factor kappaB) zeta] is a nuclear protein that is induced upon stimulation of TLRs (Toll-like receptors) and IL (interleukin)-1 receptor. IkappaB-zeta harbours C-terminal ankyrin repeats that interact with NF-kappaB. Our recent studies have shown that, upon stimulation, IkappaB-zeta is essential for the induction of a subset of inflammatory genes, represented by IL-6, whereas it inhibits the expression of TNF (tumour necrosis factor)-alpha. In the present study, we investigated mechanisms that determine the different functions of IkappaB-zeta. We found that co-expression of IkappaB-zeta and the NF-kappaB subunits synergistically activates transcription of the hBD-2 (human beta-defensin 2) and NGAL (neutrophil gelatinase-associated lipocalin) genes, whereas it inhibits transcription of E-selectin. Reporter analyses indicated that, in addition to an NF-kappaB-binding site, a flanking C/EBP (CCAAT/enhancer-binding protein)-binding site in the promoters is essential for the IkappaB-zeta-mediated transcriptional activation. Using an artificial promoter consisting of the NF-kappaB- and C/EBP-binding sites, transcriptional activation was observed upon co-transfection with IkappaB-zeta and NF-kappaB, indicating that these sequences are minimal elements that confer the IkappaB-zeta-mediated transcriptional activation. Chromatin immunoprecipitation assays and knockdown experiments showed that both IkappaB-zeta and the NF-kappaB subunits were recruited to the NGAL promoter and were essential for the transcriptional activation of the hBD-2 and NGAL promoters on stimulation with IL-1beta. The activation of the NGAL promoter by transfection of IkappaB-zeta and NF-kappaB was suppressed in C/EBPbeta-depleted cells. Thus IkappaB-zeta acts as an essential transcriptional activator by forming a complex with NF-kappaB on promoters harbouring the NF-kappaB- and C/EBP-binding sites, upon stimulation of TLRs or IL-1 receptor.
Mesh Headings (Keywords): Acute-Phase Proteins, Binding Sites, CCAAT-Enhancer-Binding Proteins, Cell Line, Humans, Lipocalins, NF-kappa B, Nuclear Proteins, Promoter Regions (Genetics), Protein Binding, Proto-Oncogene Proteins, RNA Interference, RNA, Messenger, Trans-Activation (Genetics), Transcription, Genetic
Check for Full Text / PubMed Unique Identifier (PMID): 17447895
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