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首页> 外文期刊>Molecular and Cellular Biology >The p65 (RelA) Subunit of NF-κB Interacts with the Histone Deacetylase (HDAC) Corepressors HDAC1 and HDAC2 To Negatively Regulate Gene Expression
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The p65 (RelA) Subunit of NF-κB Interacts with the Histone Deacetylase (HDAC) Corepressors HDAC1 and HDAC2 To Negatively Regulate Gene Expression

机译：NF-κB的p65（RelA）亚基与组蛋白去乙酰化酶（HDAC）协同抑制剂HDAC1和HDAC2相互作用，以负调控基因表达。

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Regulation of NF-κB transactivation function is controlled at several levels, including interactions with coactivator proteins. Here we show that the transactivation function of NF-κB 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-κB-dependent reporter gene. Chromatin immunoprecipitation (ChIP) assays show that TSA treatment causes hyperacetylation of the wild-type integrated NF-κB-dependent reporter but not of a mutant version in which the NF-κB binding sites were mutated. Expression of HDAC1 and HDAC2 repressed tumor necrosis factor (TNF)-induced NF-κB-dependent gene expression. Consistent with this, we show that HDAC1 and HDAC2 target NF-κB through a direct association of HDAC1 with the Rel homology domain of p65. HDAC2 does not interact with NF-κB directly but can regulate NF-κB 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-κB-regulated interleukin-8 (IL-8) gene. Similar to the wild-type integrated NF-κB-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-κB is regulated in part through its association with HDAC corepressor proteins. Moreover, it suggests that the association of NF-κB with the HDAC1 and HDAC2 corepressor proteins functions to repress expression of NF-κB-regulated genes as well as to control the induced level of expression of these genes.
机译：NF-κB反式激活功能的调节被控制在几个水平上，包括与共激活蛋白的相互作用。在这里，我们显示NF-κB的反式激活功能还通过p65（RelA）亚基与组蛋白脱乙酰基酶（HDAC）核心加压蛋白的相互作用来调节。我们的结果表明，曲古抑菌素A（TSA）对HDAC活性的抑制导致基础和诱导表达的整合NF-κB依赖性报告基因的表达增加。染色质免疫沉淀（ChIP）分析表明，TSA处理可引起野生型整合的NF-κB依赖性报告基因的过度乙酰化，但不会引起NF-κB结合位点发生突变的突变体的过度乙酰化。 HDAC1和HDAC2的表达抑制了肿瘤坏死因子（TNF）诱导的NF-κB依赖性基因表达。与此相符，我们表明HDAC1和HDAC2通过HDAC1与p65的Rel同源域的直接关联而靶向NF-κB。 HDAC2不直接与NF-κB相互作用，但可以通过与HDAC1的结合来调节NF-κB的活性。最后，我们显示了用TSA抑制HDAC活性会导致基础和TNF诱导的NF-κB调节白介素8（IL-8）基因表达的增加。与野生型整合的依赖NF-κB的报告基因相似，ChIP分析表明TSA处理可导致IL-8启动子过度乙酰化。这些数据表明，NF-κB的反式激活功能部分地通过其与HDAC抑癌蛋白的结合来调节。此外，这表明NF-κB与HDAC1和HDAC2共抑制蛋白的结合起抑制NF-κB调节基因的表达以及控制这些基因的诱导表达水平的作用。

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