Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy, Amarillo, TX 79106, USA.
Oncogene. 2013 May 30;32(22):2782-91. doi: 10.1038/onc.2012.289. Epub 2012 Jul 9.
There is an increasing interest in determining the role of ribosomal proteins (RPs) in the regulation of MDM2-p53 pathway in coordinating cellular response to stress. Herein, we report a novel regulatory role of ribosomal protein S25 (RPS25) in MDM2-mediated p53 degradation and a feedback regulation of S25 by p53. We demonstrated that S25 interacted with MDM2 and inhibited its E3 ligase activity, resulting in the reduction of MDM2-mediated p53 ubiquitination and the stabilization and activation of p53. S25, MDM2 and p53 formed a ternary complex following ribosomal stress. The nucleolar localization and MDM2-binding domains of S25 were critical for its role in MDM2-mediated p53 regulation. Knockdown of S25 by siRNA attenuated the induction and activation of p53 following ribosomal stress. S25 stabilized and cooperated with MDMX to regulate MDM2 E3 ligase activity. Furthermore, S25 was identified to be a transcriptional target of p53; p53 directly bound to S25 promoter and suppressed S25 expression. Our results suggest that there is a S25-MDM2-p53 regulatory feedback loop, which may have an important role in cancer development and progression.
人们越来越关注核糖体蛋白（RPs）在调节 MDM2-p53 通路以协调细胞对应激的反应中的作用。在此，我们报告了核糖体蛋白 S25（RPS25）在 MDM2 介导的 p53 降解中的新的调节作用，以及 p53 对 S25 的反馈调节。我们证明 S25 与 MDM2 相互作用并抑制其 E3 连接酶活性，导致 MDM2 介导的 p53 泛素化减少，p53 稳定和激活。核糖体应激后，S25、MDM2 和 p53 形成三元复合物。S25 的核仁定位和 MDM2 结合结构域对于其在 MDM2 介导的 p53 调节中的作用至关重要。siRNA 敲低 S25 可减弱核糖体应激后 p53 的诱导和激活。S25 稳定并与 MDMX 合作调节 MDM2 E3 连接酶活性。此外，S25 被鉴定为 p53 的转录靶标；p53 直接结合 S25 启动子并抑制 S25 表达。我们的结果表明，存在 S25-MDM2-p53 调节反馈回路，它可能在癌症的发生和发展中起重要作用。
