New Molecular Bridge between RelA/p65 and NF-κB Target Genes via Histone Acetyltransferase TIP60 Cofactor
New Molecular Bridge between RelA/p65 and NF-κB Target Genes via Histone Acetyltransferase TIP60 Cofactor
复制标题
DOI：
10.1074/jbc.m111.278465
复制
发表时间：
2012-03-02
影响因子：
4.8
通讯作者：
Choi, Kyung-Hee
中科院分区：
文献类型：
--
作者：
Kim, Jung-Woong;Jang, Sang-Min;Choi, Kyung-Hee
核因子-κ B（NF-κ B）家族参与许多基因的表达，参与发育、凋亡、炎症反应和肿瘤发生。在这项研究中，我们确定了四个NF-κ B B靶基因，是由TIP 60调节。我们还发现，TIP 60与NF-κ B B RelA/p65亚基相互作用，并通过蛋白质-蛋白质相互作用增加其转录活性。虽然TIP 60使用其组蛋白乙酰转移酶结构域与RelA/p65结合，但TIP 60不直接乙酰化RelA/p65。然而，TIP 60在TNF-α依赖性NF-κ B信号通路中维持乙酰化Lys 310 RelA/p65水平。在染色质免疫沉淀测定中，TIP 60主要在TNF-α刺激中被募集到IL-6、IL-8、C-IAP 1和XIAP启动子，随后是组蛋白H3和H4的乙酰化。染色质重塑TIP 60涉及乙酰基-Lys-310 RelA/p65的顺序招募到其靶基因启动子。肝癌组织中TIP 60的表达上调与乙酰化赖氨酸310 RelA/p65的表达相关。总之，这些结果表明，TIP 60通过与RelA/p65的蛋白质相互作用参与NF-κ B B途径，并且它调节RelA/p65在NF-κ B依赖性基因表达中的转录活性。
The nuclear factor-kappa B (NF-kappa B) family is involved in the expressions of numerous genes, in development, apoptosis, inflammatory responses, and oncogenesis. In this study we identified four NF-kappa B target genes that are modulated by TIP60. We also found that TIP60 interacts with the NF-kappa B 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 Lys310 RelA/p65 levels in the TNF-alpha-dependent NF-kappa B signaling pathway. In chromatin immunoprecipitation assay, TIP60 was primarily recruited to the IL-6, IL-8, C-IAP1, and XIAP promoters in TNF-alpha 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-kappa B pathway through protein interaction with RelA/p65 and that it modulates the transcriptional activity of RelA/p65 in NF-kappa B-dependent gene expression.