Potentiation of tumor necrosis factor-induced NF-kappa B activation by deacetylase inhibitors is associated with a delayed cytoplasmic reappearance of I kappa B alpha
[en] Previous studies have implicated acetylases and deacetylases in regulating the transcriptional activity of NF-kappaB. Here, we show that inhibitors of deacetylases such as trichostatin A (TSA) and sodium butyrate (NaBut) potentiated TNF-induced expression of several natural NF-kappaB-driven promoters. This transcriptional synergism observed between TNF and TSA (or NaBut) required intact kappaB sites in all promoters tested and was biologically relevant as demonstrated by RNase protection on two instances of endogenous NF-kappaB-regulated gene transcription. Importantly, TSA prolonged both TNF-induced DNA-binding activity and the presence of NF-kappaKB in the nucleus. We showed that the p65 subunit of NF-kappaB was acetylated in vivo. However, this acetylation was weak, suggesting that other mechanisms could be implicated in the potentiated binding and transactivation activities of NF-kappaB after TNF plus TSA versus TNF treatment. Western blot and immunofluorescence confocal microscopy experiments revealed a delay in the cytoplasmic reappearance of the IkappaBalpha inhibitor that correlated temporally with the prolonged intranuclear binding and presence of NF-kappaB. This delay was due neither to a defect in IkappaBalpha mRNA production nor to a nuclear retention of IkappaBalpha but was rather due to a persistent proteasome-mediated degradation of IkappaBalpha. A prolongation of IkappaB kinase activity could explain, at least partially, the delayed IkappaBalpha cytoplasmic reappearance observed in presence of TNF plus TSA.
Research center :
Giga-Signal Transduction - ULiège
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Adam, Emmanuelle
Quivy, Vincent
Bex, Françoise
Chariot, Alain ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale
Collette, Yves
Vanhulle, Caroline
Haterte, Stéphanie ; Université de Liège - ULiège > Département des sciences de la santé publique > Informatique médicale et biostatistique
Goffin, Véronique ; Centre Hospitalier Universitaire de Liège - CHU > Dermatopathologie
Potentiation of tumor necrosis factor-induced NF-kappa B activation by deacetylase inhibitors is associated with a delayed cytoplasmic reappearance of I kappa B alpha
Publication date :
September 2003
Journal title :
Molecular and Cellular Biology
ISSN :
0270-7306
eISSN :
1098-5549
Publisher :
Amer Soc Microbiology, Washington, United States - Washington
Volume :
23
Issue :
17
Pages :
6200-6209
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] Télévie [BE]
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