Abstract
The nuclear factor-κB (NF-κB) family is involved in the expressions of numerous genes, in development, apoptosis, inflammatory responses, and oncogenesis. In this study we identified four NF-κB target genes that are modulated by TIP60. We also found that TIP60 interacts with the NF-κB RelA/p65 subunit and increases its transcriptional activity through protein-protein interaction. Although TIP60 binds with RelA/p65 using its histone acetyltransferase domain, TIP60 does not directly acetylate RelA/p65. However, TIP60 maintained acetylated Lys-310 RelA/p65 levels in the TNF-α-dependent NF-κB signaling pathway. In chromatin immunoprecipitation assay, TIP60 was primarily recruited to the IL-6, IL-8, C-IAP1, and XIAP promoters in TNF-α stimulation followed by acetylation of histones H3 and H4. Chromatin remodeling by TIP60 involved the sequential recruitment of acetyl-Lys-310 RelA/p65 to its target gene promoters. Furthermore, we showed that up-regulated TIP60 expression was correlated with acetyl-Lys-310 RelA/p65 expressions in hepatocarcinoma tissues. Taken together these results suggest that TIP60 is involved in the NF-κB pathway through protein interaction with RelA/p65 and that it modulates the transcriptional activity of RelA/p65 in NF-κB-dependent gene expression.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acetylation
-
Carcinoma, Hepatocellular / genetics
-
Carcinoma, Hepatocellular / metabolism*
-
Gene Expression Regulation, Neoplastic*
-
HEK293 Cells
-
Hep G2 Cells
-
Histone Acetyltransferases / genetics
-
Histone Acetyltransferases / metabolism*
-
Histones / genetics
-
Histones / immunology
-
Humans
-
Inhibitor of Apoptosis Proteins / biosynthesis
-
Inhibitor of Apoptosis Proteins / genetics
-
Interleukin-6 / biosynthesis
-
Interleukin-6 / genetics
-
Interleukin-8 / biosynthesis
-
Interleukin-8 / genetics
-
Liver Neoplasms / genetics
-
Liver Neoplasms / metabolism*
-
Lysine Acetyltransferase 5
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / metabolism*
-
Promoter Regions, Genetic*
-
Transcription Factor RelA / genetics
-
Transcription Factor RelA / metabolism*
-
Tumor Necrosis Factor-alpha / genetics
-
Tumor Necrosis Factor-alpha / metabolism
-
Up-Regulation / genetics
-
X-Linked Inhibitor of Apoptosis Protein / biosynthesis
-
X-Linked Inhibitor of Apoptosis Protein / genetics
Substances
-
CXCL8 protein, human
-
Histones
-
IL6 protein, human
-
Inhibitor of Apoptosis Proteins
-
Interleukin-6
-
Interleukin-8
-
Neoplasm Proteins
-
RELA protein, human
-
Transcription Factor RelA
-
Tumor Necrosis Factor-alpha
-
X-Linked Inhibitor of Apoptosis Protein
-
XIAP protein, human
-
Histone Acetyltransferases
-
KAT5 protein, human
-
Lysine Acetyltransferase 5