Klinikum rechts der Isar, II, Medizinische Klinik, Technische Universität München, München, Germany.
Oncogene. 2010 May 13;29(19):2795-806. doi: 10.1038/onc.2010.46. Epub 2010 Mar 1.
Nuclear factor-kappaB (NF-kappaB) 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-kappaB 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-kappaB activity during S-phase checkpoint activation involving ataxia-telangiectasia mutated and checkpoint kinase-1. Accordingly, the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) also triggers formation of a transcriptionally active complex containing nuclear p65 and p53 on kappaB response elements. Gene expression analyses revealed that, independent of NF-kappaB activation in the cytosol, TNF-induced NF-kappaB-directed gene expression relies on p53. Hence, p53 is unexpectedly necessary for NF-kappaB-mediated gene expression induced by atypical and classical stimuli. Remarkably, data from gain- and loss-of function approaches argue that anti-apoptotic NF-kappaB 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.
核因子-κB（NF-κB）和 p53 对癌症的发生和发展起着至关重要的作用。明确这些转录因子之间的相互作用可以扩展我们对肿瘤发生的分子机制的认识。在这里，我们表明复制应激的诱导激活了 NF-κB p65，并触发了它与核内 p53 的相互作用。使用敲除细胞的实验表明，p65 和 p53 都需要在涉及共济失调毛细血管扩张突变和检查点激酶-1 的 S 期检查点激活期间增强 NF-κB 活性。相应地，促炎细胞因子肿瘤坏死因子-α（TNF-α）也触发了含有核 p65 和 p53 的转录活性复合物的形成，该复合物位于 kappaB 反应元件上。基因表达分析显示，独立于细胞质中 NF-κB 的激活，TNF 诱导的 NF-κB 定向基因表达依赖于 p53。因此，出乎意料的是，p53 对于由非典型和经典刺激诱导的 NF-κB 介导的基因表达是必需的。值得注意的是，来自增益和缺失功能方法的数据表明，经常在肿瘤中发现的 p53 热点突变体持续引发抗凋亡 NF-κB p65 活性。我们的观察结果为为什么在各种起源的肿瘤中出现 p53 突变而不是 p53 缺失这一悬而未决的问题提供了一些解释。
