[en] NF-kappaB is a crucial transcription factor tightly regulated by protein
interactions and post-translational modifications, like phosphorylation
and acetylation. A previous study has shown that trichostatin
A (TSA), a histone deacetylase inhibitor, potentiates
tumor necrosis factor (TNF) alpha-elicited NF-kappaB activation and
delays IkappaBalpha cytoplasmic reappearance. Here, we demonstrated
that TSA also prolongs NF-kappaB activation when induced by the
insulino-mimetic pervanadate (PV), a tyrosine phosphatase inhibitor
that initiates an atypical NF-kappaB signaling. This extension is
similarly correlated with delayed IkappaBalpha cytoplasmic reappearance.
However, whereas TSA causes a prolonged IKK activity when
addedtoTNFalpha, it does notwhenaddedtoPV.Instead, quantitative
reverse transcriptase-PCR revealed a decrease of ikappabalphamRNAlevel
after TSA addition to PV stimulation. This synthesis deficit of the
inhibitor could explain the sustained NF-kappaB residence in the
nucleus. In vivo analysis by chromatin immunoprecipitation assays
uncovered that, forPVinduction but not forTNFalpha, the presence of
TSA provokes several impairments on the ikappabalphapromoter: (i) diminution
of RNA Pol II recruitment; (ii) reduced acetylation and
phosphorylation of histone H3-Lys14 and -Ser10, respectively; (iii)
decreased presence of phosphorylated p65-Ser536; and (iv) reduction
of IKKalphabinding. The recruitment of these proteins on the
icam-1 promoter, another NF-kappaB-regulated gene, is not equally
affected, suggesting a promoter specificity of PV with TSA stimulation.
Taken together, these data suggest that TSA acts differently
depending on the NF-kappaB pathway and the targeted promoter in
question. This indicates that one overall histone deacetylase role is
to inhibit NF-kappaB activation by molecular mechanisms specific of
the stimulus and the promoter.
Research Center/Unit :
Giga-Signal Transduction - ULiège
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Horion, Julie ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Piette, Jacques ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Virologie - Immunologie - Département des sciences de la vie - GIGA-Research
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