Histone deacetylase inhibitor trichostatin A sustains sodium pervanadate-induced NF-κB activation by delaying IκBα mRNA resynthesis -: Comparison with tumor necrosis factor α
Histone deacetylase inhibitor trichostatin A sustains sodium pervanadate-induced NF-κB activation by delaying IκBα mRNA resynthesis -: Comparison with tumor necrosis factor α
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DOI：
10.1074/jbc.m609166200
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发表时间：
2007-05-25
影响因子：
4.8
通讯作者：
Habraken, Yvette
中科院分区：
文献类型：
--
作者：
Horion, Julie;Gloire, Geoffrey;Habraken, Yvette
NF-κ B B是一种重要的转录因子，受蛋白质相互作用和翻译后修饰（如磷酸化和乙酰化）的严格调控。先前的研究表明，组蛋白脱乙酰酶抑制剂--在这里，我们证明TSA也抑制NF-κ B激活时，诱导的拟胰岛素过钒酸盐（PV），酪氨酸磷酸酶抑制剂，启动一个非典型的NF-κ B信号。这种延伸与延迟的I κ B α细胞质再现类似相关。然而，当TSA加入TNF α中时，它会导致IKK活性延长，而当加入PV中时则不会。相反，定量逆转录酶-PCR显示，在TSA加入PV刺激后，i kappa B α mRNA水平降低。这种抑制剂的合成缺陷可以解释NF-κ B在细胞核中的持续驻留。通过染色质免疫沉淀分析的体内分析发现，对于PV诱导，而不是对于TNF α，TSA的存在引起i κ B α启动子上的几种损伤：（i）RNA Pol II募集减少;（ii）组蛋白H3-Lys（14）和-Ser（10）的乙酰化和磷酸化分别减少;（iii）磷酸化p65-Ser 536的存在减少;和（iv）IKK α结合的减少。这些蛋白质在ICAM-1启动子（另一个NF-κ B调节基因）上的募集并没有受到同等影响，这表明TSA刺激对PV的启动子特异性有影响。综上所述，这些数据表明TSA的作用不同，这取决于NF-κ B途径和靶向启动子的问题。这表明组蛋白脱乙酰酶的一个总体作用是通过刺激和启动子特异性的分子机制抑制NF-κ B活化。
NF-kappa B is a crucial transcription factor tightly regulated by protein interactions and post-translational modifications, like phosphorylation and acetylation. A previous study has shown that trichostatin A (TSA), a histone deacetylase inhibitor, potentiates tumor necrosis factor (TNF) alpha-elicited NF-kappa B activation and delays I kappa B alpha cytoplasmic reappearance. Here, we demonstrated that TSA also prolongs NF-kappa B activation when induced by the insulino-mimetic pervanadate (PV), a tyrosine phosphatase inhibitor that initiates an atypical NF-kappa B signaling. This extension is similarly correlated with delayed I kappa B alpha cytoplasmic reappearance. However, whereas TSA causes a prolonged IKK activity when added to TNF alpha, it does not when added to PV. Instead, quantitative reverse transcriptase-PCR revealed a decrease of i kappa b alpha mRNA level after TSA addition to PV stimulation. This synthesis deficit of the inhibitor could explain the sustained NF-kappa B residence in the nucleus. In vivo analysis by chromatin immunoprecipitation assays uncovered that, for PV induction but not for TNF alpha, the presence of TSA provokes several impairments on the i kappa b alpha promoter: (i) diminution of RNA Pol II recruitment; (ii) reduced acetylation and phosphorylation of histone H3-Lys(14) and -Ser(10), respectively; (iii) decreased presence of phosphorylated p65-Ser536; and (iv) reduction of IKK alpha binding. The recruitment of these proteins on the icam-1 promoter, another NF-kappa B-regulated gene, is not equally affected, suggesting a promoter specificity of PV with TSA stimulation. Taken together, these data suggest that TSA acts differently depending on the NF-kappa B pathway and the targeted promoter in question. This indicates that one overall histone deacetylase role is to inhibit NF-kappa B activation by molecular mechanisms specific of the stimulus and the promoter.