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Horion J, Gloire G, El Mjiyad N, Quivy V,
Vermeulen L, Vanden Berghe W, Haegeman G, Van
Lint C, Piette J, Habraken Y.
Histone deacetylase inhibitor trichostatin A
sustains sodium pervanadate-induced NF-kappaB
activation by delaying IkappaBalpha mRNA
resynthesis: comparison with tumor necrosis
factor alpha.
J Biol Chem. 2007 May 25;282(21):15383-93
Laboratory of Virology and Immunology, GIGA-R, University of
Liège, 4000 Liège, Belgium.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, a
histone deacetylase inhibitor, potentiates tumor necrosis factor
(TNF) alpha-elicited NF-kappaB activation and delays
IkappaBalpha cytoplasmic reappearance. Here, we demonstrated
that trichostatin A 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
trichostatin A causes a prolonged IKK activity when added to
TNFalpha, it does not when added to PV. Instead, quantitative
reverse transcriptase-PCR revealed a decrease of ikappabalpha
mRNA level after trichostatin A 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, for PV
induction but not for TNFalpha, the presence of trichostatin A
provokes several impairments on the ikappabalpha promoter: (i)
diminution of RNA Pol II recruitment; (ii) reduced acetylation
and phosphorylation of histone H3-Lys(14) and -Ser(10),
respectively; (iii) decreased presence of phosphorylated
p65-Ser(536); and (iv) reduction of IKKalpha binding. 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 trichostatin A stimulation.
Taken together, these data suggest that trichostatin A 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.
PMID: 17409387
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