The tumor suppressor p53 plays a pivotal role in tumor prevention. The activity of p53 is mainly restrained by the ubiquitin E3 ligase Mdm2. However, it is not well understood how the Mdm2-p53 pathway is intricately regulated. Here we report that the RNA binding protein RALY functions as an oncogenic factor in lung cancer. RALY simultaneously binds to Mdm2 and the deubiquitinating enzyme USP7. Via these interactions, RALY not only stabilizes Mdm2 by stimulating the deubiquitinating activity of USP7 toward Mdm2 but also increases the trans-E3 ligase activity of Mdm2 toward p53. Consequently, RALY enhances Mdm2-mediated ubiquitination and degradation of p53. Functionally, RALY promotes lung tumorigenesis, at least partially, via negative regulation of p53. These findings suggest that RALY destabilizes p53 by modulating the function of Mdm2 at multiple levels. Our study also indicates a critical role for RALY in promoting lung tumorigenesis via p53 inhibition.

抑癌基因p53在肿瘤预防中发挥着关键作用。p53的活性主要受到泛素E3连接酶Mdm2的抑制。然而，目前尚不清楚 Mdm2-p53 通路是如何复杂调节的。在这里，我们报道 RNA 结合蛋白 RALY 作为肺癌的致癌因子。RALY 同时结合 Mdm2 和去泛素化酶 USP7。通过这些相互作用，RALY 不仅通过刺激 USP7 对 Mdm2 的去泛素化活性来稳定 Mdm2，而且还增加Mdm2 对 p53 的反式E3 连接酶活性。因此，RALY 增强 Mdm2 介导的 p53 泛素化和降解。从功能上讲，RALY 至少部分通过 p53 的负调节促进肺部肿瘤发生。这些发现表明 RALY 通过在多个水平上调节 Mdm2 的功能来破坏 p53 的稳定性。我们的研究还表明 RALY 通过抑制 p53 在促进肺部肿瘤发生中发挥关键作用。