title: 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.
abstract: Previous studies have implicated acetylases and deacetylases in regulating the transcriptional activity of NF-kappa B. Here, we show that inhibitors of deacetylases such as trichostatin A (TSA) and sodium butyrate (NaBut) potentiated TNF-induced expression of several natural NF-kappa B-driven promoters. This transcriptional synergism observed between TNF and TSA (or NaBut) required intact kappa B sites in all promoters tested and was biologically relevant as demonstrated by RNase protection on two instances of endogenous NF-kappa B-regulated gene transcription. Importantly, TSA prolonged both TNF-induced DNA-binding activity and the presence of NF-kappa B in the nucleus. We showed that the p65 subunit of NF-kappa B 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-kappa B after TNF plus TSA versus TNF treatment. Western blot and immunofluorescence confocal microscopy experiments revealed a delay in the cytoplasmic reappearance of the I kappa B alpha inhibitor that correlated temporally with the prolonged intranuclear binding and presence of NF-kappa B. This delay was due neither to a defect in I kappa B alpha mRNA production nor to a nuclear retention of I kappa B alpha but was rather due to a persistent proteasome-mediated degradation of I kappa B alpha. A prolongation of I kappa B kinase activity could explain, at least partially, the delayed I kappa B alpha cytoplasmic reappearance observed in presence of TNF plus TSA.
authors.affiliation: Institut de Biologie et de Médecine Moléculaires, Service de Chimie Biologique, Laboratoire de Virologie Moléculaire, Université Libre de Bruxelles, 6041 Gosselies, Belgium.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Adam
authors.forename: Vincent
authors.initials: V
authors.lastname: Quivy
authors.forename: Françoise
authors.initials: F
authors.lastname: Bex
authors.forename: Alain
authors.initials: A
authors.lastname: Chariot
authors.forename: Yves
authors.initials: Y
authors.lastname: Collette
authors.forename: Caroline
authors.initials: C
authors.lastname: Vanhulle
authors.forename: Sonia
authors.initials: S
authors.lastname: Schoonbroodt
authors.forename: Véronique
authors.initials: V
authors.lastname: Goffin
authors.forename: Thi Liên-Anh
authors.initials: TL
authors.lastname: Nguyên
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Gloire
authors.forename: Géraldine
authors.initials: G
authors.lastname: Carrard
authors.forename: Bertrand
authors.initials: B
authors.lastname: Friguet
authors.forename: Yvan
authors.initials: Y
authors.lastname: De Launoit
authors.forename: Arsène
authors.initials: A
authors.lastname: Burny
authors.forename: Vincent
authors.initials: V
authors.lastname: Bours
authors.forename: Jacques
authors.initials: J
authors.lastname: Piette
authors.forename: Carine
authors.initials: C
authors.lastname: Van Lint
mesh_terms: D000818:Animals; D020148:Butyric Acid / Q000494:pharmacology; D003546:Cysteine Endopeptidases; D003593:Cytoplasm / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D020672:I-kappa B Proteins; D007976:Leupeptins; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D020148:Butyric Acid; D000072000:NF-KappaB Inhibitor alpha; C012589:trichostatin A; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D020928:Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde