Cross talk between stimulated NF-κB and the tumor suppressor p53
Cross talk between stimulated NF-κB and the tumor suppressor p53
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DOI：
10.1038/onc.2010.46
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发表时间：
2010-05-01
期刊：
影响因子：
8
通讯作者：
Kraemer, O. H.
中科院分区：
文献类型：
--
作者：
Schneider, G.;Henrich, A.;Kraemer, O. H.
核因子κ B （nf - κ B）和p53在癌症的发生和发展中起着至关重要的作用。确定这些转录因子之间的串扰可以扩展我们对肿瘤发生的分子机制的认识。在这里，我们证明了复制应激的诱导激活NF-kappa B p65并触发其与细胞核中p53的相互作用。敲除细胞的实验表明，p65和p53都是s期检查点激活过程中NF-kappa B活性增强所必需的，涉及不相容性血管扩张突变和检查点激酶-1。因此，促炎细胞因子肿瘤坏死因子α (tnf - α)也会触发含有核p65和p53的转录活性复合物在jB反应元件上的形成。基因表达分析显示，tnf诱导的NF-kappa B定向基因表达依赖于p53，而不依赖于胞质中NF-kappa B的活化。因此，对于非典型和经典刺激诱导的nf - κ b介导的基因表达，p53是出乎意料的必要条件。值得注意的是，来自功能增益和功能丧失方法的数据表明，抗凋亡NF-kappa B p65活性是由肿瘤中常见的p53热点突变体组成性地激发的。我们的观察结果解释了为什么p53突变而不是p53缺失出现在各种起源的肿瘤中的突出问题。中华肿瘤杂志（2010）29,2795-2806；doi: 10.1038 / onc.2010.46;2010年3月1日在线发布
Nuclear factor-kappa B (NF-kappa B) and p53 critically determine cancer development and progression. Defining the cross talk between these transcription factors can expand our knowledge on molecular mechanisms of tumorigenesis. Here, we show that induction of replicational stress activates NF-kappa B p65 and triggers its interaction with p53 in the nucleus. Experiments with knockout cells show that p65 and p53 are both required for enhanced NF-kappa B activity during S-phase checkpoint activation involving ataxiatelangiectasia mutated and checkpoint kinase-1. Accordingly, the pro-inflammatory cytokine tumor necrosis factora alpha (TNF-alpha) also triggers formation of a transcriptionally active complex containing nuclear p65 and p53 on jB response elements. Gene expression analyses revealed that, independent of NF-kappa B activation in the cytosol, TNFinduced NF-kappa B-directed gene expression relies on p53. Hence, p53 is unexpectedly necessary for NF-kappa B-mediated gene expression induced by atypical and classical stimuli. Remarkably, data from gain- and loss-of function approaches argue that anti-apoptotic NF-kappa B p65 activity is constitutively evoked by a p53 hot-spot mutant frequently found in tumors. Our observations suggest explanations for the outstanding question why p53 mutations rather than p53 deletions arise in tumors of various origins. Oncogene (2010) 29, 2795-2806; doi: 10.1038/onc.2010.46; published online 1 March 2010