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
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
PubMed ID: 18779315
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