HNF-4 (hepatocyte nuclear factor 4) is a key regulator of liver-specific gene expression in mammals. We have shown previously that the activity of the human APOC3 (apolipoprotein C-III) promoter is positively regulated by the anti-inflammatory cytokine TGFβ (transforming growth factor β) and its effectors Smad3 (similar to mothers against decapentaplegic 3) and Smad4 proteins via physical and functional interactions between Smads and HNF-4. We now show that the pro-inflammatory cytokine TNFα (tumour necrosis factor α) antagonizes TGFβ for the regulation of APOC3 gene expression in hepatocytes. TNFα was a strong inhibitor of the activity of apolipoprotein promoters that harbour HNF-4 binding sites and this inhibition required HNF-4. Using specific inhibitors of TNFα-induced signalling pathways, it was shown that inhibition of the APOC3 promoter by TNFα involved NF-κB (nuclear factor κB). Latent membrane protein 1 of the Epstein–Barr virus, which is an established potent activator of NF-κB as well as wild-type forms of various NF-κB signalling mediators, also inhibited strongly the APOC3 promoter and the transactivation function of HNF-4. TNFα had no effect on the stability or the nuclear localization of HNF-4 in HepG2 cells, but inhibited the binding of HNF-4 to the proximal APOC3 HRE (hormone response element). Using the yeast-transactivator-GAL4 system, we showed that both AF-1 and AF-2 (activation functions 1 and 2) of HNF-4 are inhibited by TNFα and that this inhibition was abolished by overexpression of different HNF-4 co-activators, including PGC-1 (peroxisome-proliferator-activated-receptor-γ co-activator 1), CBP [CREB (cAMP-response-element-binding protein) binding protein] and SRC3 (steroid receptor co-activator 3). In summary, our findings indicate that TNFα, or other factors that trigger an NF-κB response in hepatic cells, inhibit the transcriptional activity of the APOC3 and other HNF-4-dependent promoters and that this inhibition could be accounted for by a decrease in DNA binding and the down-regulation of the transactivation potential of the AF-1 and AF-2 domains of HNF-4.
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Research Article|
August 29 2006
Inhibition of hepatocyte nuclear factor 4 transcriptional activity by the nuclear factor κB pathway Available to Purchase
Varvara Nikolaidou-Neokosmidou;
Varvara Nikolaidou-Neokosmidou
1Department of Basic Sciences, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology Hellas (IMBB-FORTH), Heraklion 71003, Crete, Greece
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Vassilis I. Zannis;
Vassilis I. Zannis
1Department of Basic Sciences, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology Hellas (IMBB-FORTH), Heraklion 71003, Crete, Greece
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Dimitris Kardassis
Dimitris Kardassis
1
1Department of Basic Sciences, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology Hellas (IMBB-FORTH), Heraklion 71003, Crete, Greece
1To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
January 30 2006
Revision Received:
June 01 2006
Accepted:
June 13 2006
Accepted Manuscript online:
June 13 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 398 (3): 439–450.
Article history
Received:
January 30 2006
Revision Received:
June 01 2006
Accepted:
June 13 2006
Accepted Manuscript online:
June 13 2006
Citation
Varvara Nikolaidou-Neokosmidou, Vassilis I. Zannis, Dimitris Kardassis; Inhibition of hepatocyte nuclear factor 4 transcriptional activity by the nuclear factor κB pathway. Biochem J 15 September 2006; 398 (3): 439–450. doi: https://doi.org/10.1042/BJ20060169
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