The ING4 tumor suppressor attenuates NF-kappaB activity at the promoters of target genes.

The NF-kappaB family mediates immune and inflammatory responses. In many cancers, NF-kappaB is constitutively activated and induces the expression of genes that facilitate tumorigenesis. ING4 is a tumor suppressor that is absent or mutated in several cancers. Herein, we demonstrate that in human gliomas, NF-kappaB is constitutively activated, ING4 expression ...
is negligible, and NF-kappaB-regulated gene expression is elevated. We demonstrate that an ING4 and NF-kappaB interaction exists but does not prevent NF-kappaB activation, nuclear translocation, or DNA binding. Instead, ING4 and NF-kappaB bind simultaneously at NF-kappaB-regulated promoters, and this binding correlates with reductions in p65 phosphorylation, p300, and the levels of acetylated histones and H3-Me3K4, while enhancing the levels of HDAC-1 at these promoters. Using a knockdown approach, we correlate reductions in ING4 protein levels with increased basal and inducible NF-kappaB target gene expression. Collectively, these data suggest that ING4 may specifically regulate the activity of NF-kappaB molecules that are bound to target gene promoters.
Mesh Terms:
Cell Cycle Proteins, Cell Line, Tumor, Cell Nucleus, Cyclooxygenase 2, Dose-Response Relationship, Drug, E1A-Associated p300 Protein, Gene Expression Regulation, Neoplastic, Genes, Neoplasm, Glioma, Histone Deacetylase 1, Histone Deacetylases, Histones, Homeodomain Proteins, Humans, Matrix Metalloproteinase 9, NF-kappa B, Promoter Regions, Genetic, Protein Binding, Protein Transport, RNA, Small Interfering, Transcription Factor RelA, Transcription, Genetic, Tumor Suppressor Proteins
Mol. Cell. Biol.
Date: Nov. 01, 2008
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