The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression.
Regulation of NF-kappaB transactivation function is controlled at several levels, including interactions with coactivator proteins. Here we show that the transactivation function of NF-kappaB is also regulated through interaction of the p65 (RelA) subunit with histone deacetylase (HDAC) corepressor proteins. Our results show that inhibition of HDAC activity with trichostatin ... A (TSA) results in an increase in both basal and induced expression of an integrated NF-kappaB-dependent reporter gene. Chromatin immunoprecipitation (ChIP) assays show that TSA treatment causes hyperacetylation of the wild-type integrated NF-kappaB-dependent reporter but not of a mutant version in which the NF-kappaB binding sites were mutated. Expression of HDAC1 and HDAC2 repressed tumor necrosis factor (TNF)-induced NF-kappaB-dependent gene expression. Consistent with this, we show that HDAC1 and HDAC2 target NF-kappaB through a direct association of HDAC1 with the Rel homology domain of p65. HDAC2 does not interact with NF-kappaB directly but can regulate NF-kappaB activity through its association with HDAC1. Finally, we show that inhibition of HDAC activity with TSA causes an increase in both basal and TNF-induced expression of the NF-kappaB-regulated interleukin-8 (IL-8) gene. Similar to the wild-type integrated NF-kappaB-dependent reporter, ChIP assays showed that TSA treatment resulted in hyperacetylation of the IL-8 promoter. These data indicate that the transactivation function of NF-kappaB is regulated in part through its association with HDAC corepressor proteins. Moreover, it suggests that the association of NF-kappaB with the HDAC1 and HDAC2 corepressor proteins functions to repress expression of NF-kappaB-regulated genes as well as to control the induced level of expression of these genes.
Mesh Terms:
3T3 Cells, Acetylation, Animals, Binding Sites, Blotting, Northern, Blotting, Western, COS Cells, Cell Line, Chromatin, Down-Regulation, Enzyme Inhibitors, Gene Expression Regulation, Enzymologic, Hela Cells, Histone Deacetylase 1, Histone Deacetylase 2, Histone Deacetylases, Humans, Hydroxamic Acids, Luciferases, Mice, NF-kappa B, Plasmids, Precipitin Tests, Protein Binding, Repressor Proteins, Transcription Factor RelA, Transcriptional Activation, Transfection
3T3 Cells, Acetylation, Animals, Binding Sites, Blotting, Northern, Blotting, Western, COS Cells, Cell Line, Chromatin, Down-Regulation, Enzyme Inhibitors, Gene Expression Regulation, Enzymologic, Hela Cells, Histone Deacetylase 1, Histone Deacetylase 2, Histone Deacetylases, Humans, Hydroxamic Acids, Luciferases, Mice, NF-kappa B, Plasmids, Precipitin Tests, Protein Binding, Repressor Proteins, Transcription Factor RelA, Transcriptional Activation, Transfection
Mol. Cell. Biol.
Date: Oct. 01, 2001
PubMed ID: 11564889
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