Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, Scotland.
Oncogene. 2012 Jun 21;31(25):3060-71. doi: 10.1038/onc.2011.482. Epub 2011 Nov 14.
Ribosomal proteins (RPs) activate the p53 tumour-suppressor protein upon disruption of the nucleolus. However, the exact mechanisms for p53 transcriptional activation through RPs are not well understood. We show that the RPL11 is rapidly but transiently recruited at promoter sites of p53-regulated genes upon nucleolar stress induced by actinomycin D (ActD). Characterisation of molecular events at p53 promoter sites shows that L11 is required for the recruitment of p53 transcriptional co-activators p300/CBP and p53 K382 acetylation. We found that direct binding to Mdm2 E3 ligase and NEDDylation of L11 are critical regulators for L11 promoter recruitment. Our data suggest that binding of L11 to Mdm2 at the promoter results in relief from Mdm2-mediated transcriptional repression of p53. Analysis of chromatin and RNA polymerase II markers suggests that L11 is involved in the initiation step of transcriptional activation. Furthermore, analysis of 36 ActD-induced genes shows that L11 and NEDD8 are global regulators of the p53 activation response. The studies provide insights on how nucleolar stress through L11 and NEDD8 can activate the transcriptional activity of p53.
核糖体蛋白（RPs）在核仁破坏时激活抑癌蛋白 p53。然而，通过 RPs 进行 p53 转录激活的确切机制尚不清楚。我们发现，在放线菌素 D（ActD）诱导的核仁应激下，RPL11 快速但短暂地募集到 p53 调控基因的启动子位点。对 p53 启动子位点的分子事件的表征表明，L11 是募集 p53 转录共激活因子 p300/CBP 和 p53 K382 乙酰化所必需的。我们发现，L11 与 Mdm2 E3 连接酶的直接结合和 L11 的 NEDDylation 是 L11 启动子募集的关键调节剂。我们的数据表明，L11 与启动子上的 Mdm2 结合导致 Mdm2 介导的 p53 转录抑制的缓解。对染色质和 RNA 聚合酶 II 标志物的分析表明，L11 参与转录激活的起始步骤。此外，对 36 个 ActD 诱导基因的分析表明，L11 和 NEDD8 是 p53 激活反应的全局调节剂。这些研究提供了关于核仁应激如何通过 L11 和 NEDD8 激活 p53 转录活性的深入了解。
