Specification of the NF-kappaB transcriptional response by p65 phosphorylation and TNF-induced nuclear translocation of IKK epsilon.
Specification of the NF-kappaB transcriptional response by p65 phosphorylation and TNF-induced nuclear translocation of IKK epsilon.
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DOI：
10.1093/nar/gkq439
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发表时间：
2010-10
影响因子：
14.9
通讯作者：
Schmitz ML
中科院分区：
文献类型：
--
作者：
Moreno R;Sobotzik JM;Schultz C;Schmitz ML
在这里，我们研究了NF-κB活性的调节后，翻译后修饰的NF-κB p65缺陷细胞与野生型蛋白或磷酸化缺陷突变体重建。NF-κB靶基因表达的分析表明，p65磷酸化单独或联合作用，以高度靶基因特异性的方式指导转录，这一发现在此讨论为NF-κB条形码假说。高分辨率显微镜和表面渲染显示丝氨酸536磷酸化p65主要在胞质溶胶中，而丝氨酸468磷酸化p65主要定位于核斑点。TNF刺激导致胞质p65激酶IKKε易位至细胞核，也易位至早幼粒细胞白血病（PML）核小体。这种可诱导的IKKε易位依赖于p65磷酸化，并被致癌PML-RARα融合蛋白阻止。染色质免疫沉淀实验揭示了IKKε与几个NF-κB靶基因的控制区的可诱导关联。在细胞核中，IKKε参与NF-κ B调控基因的表达，从而揭示了IKKε在控制核NF-κB活性方面的新作用。
Here we investigated the regulation of NF-κB activity by post-translational modifications upon reconstitution of NF-κB p65-deficient cells with the wild-type protein or phosphorylation-defect mutants. Analysis of NF-κB target gene expression showed that p65 phosphorylations alone or in combination function to direct transcription in a highly target gene-specific fashion, a finding discussed here as the NF-κB barcode hypothesis. High-resolution microscopy and surface rendering revealed serine 536 phosphorylated p65 predominantly in the cytosol, while serine 468 phosphorylated p65 mainly localized in nuclear speckles. TNF stimulation resulted in the translocation of the cytosolic p65 kinase IKKε to the nucleus and also to promyelocytic leukemia (PML) nuclear bodies. This inducible IKKε translocation was dependent on p65 phosphorylation and was prevented by the oncogenic PML-RARα fusion protein. Chromatin immunoprecipitation experiments revealed the inducible association of IKKε to the control regions of several NF-κB target genes. In the nucleus, the kinase contributes to the expression of a subset of NF-κB-regulated genes, thus revealing a novel role of IKKε for the control of nuclear NF-κB activity.
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通讯作者：
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