From the Comparative Oncology Laboratory, University of California, Davis, California 95616.
J Biol Chem. 2014 Feb 7;289(6):3164-75. doi: 10.1074/jbc.M113.524413. Epub 2013 Dec 19.
p21, a cyclin-dependent kinase inhibitor, is necessary for proper control of the cell cycle and premature senescence. Thus, p21 expression needs to be tightly controlled. In this study, we found that Rbm24, an RNA-binding protein and a target gene of the p53 protein, can regulate p21 expression via mRNA stability. Specifically, we showed that Rbm24 is induced by DNA damage and Mdm2 inhibitor Nutlin-3. We also found that p53 protein binds to and activates the promoter of the Rbm24 gene. Moreover, we found that overexpression of Rbm24 increases, whereas knockdown of Rbm24 decreases, p21 mRNA and protein expression. In addition, we demonstrated that overexpression of Rbm24 enhances the half-life of p21 transcript. Consistent with this, we provided evidence that Rbm24 binds to the 3'-untranslated region (3'-UTR) of p21 transcript and an AU/U-rich element in the p21 3'-UTR is necessary for Rbm24 to increase p21 expression. Finally, we showed that the RNA recognition motif in Rbm24 is required for binding to p21 transcript and subsequently for inducing p21 expression. Altogether, we uncovered that Rbm24 is a novel player in the p53 pathway, which may be explored to restore proper cell cycle control in p53-deficient tumors via p21.
p21 是一种细胞周期蛋白依赖性激酶抑制剂，对于细胞周期的正常控制和过早衰老至关重要。因此，p21 的表达需要受到严格的调控。在本研究中，我们发现 Rbm24（一种 RNA 结合蛋白，也是 p53 蛋白的靶基因）可以通过 mRNA 稳定性来调节 p21 的表达。具体来说，我们发现 Rbm24 可被 DNA 损伤和 Mdm2 抑制剂 Nutlin-3 诱导。我们还发现 p53 蛋白可结合并激活 Rbm24 基因的启动子。此外，我们发现 Rbm24 的过表达会增加，而 Rbm24 的敲低则会减少 p21 mRNA 和蛋白的表达。此外，我们证明 Rbm24 的过表达会增加 p21 转录本的半衰期。与之一致的是，我们提供的证据表明 Rbm24 结合到 p21 转录本的 3'-非翻译区（3'-UTR），而 p21 3'-UTR 中的 AU/U 丰富元件对于 Rbm24 增加 p21 表达是必需的。最后，我们发现 Rbm24 中的 RNA 识别基序对于与 p21 转录本结合以及随后诱导 p21 表达是必需的。总之，我们揭示了 Rbm24 是 p53 通路中的一个新成员，这可能为通过 p21 来恢复 p53 缺陷型肿瘤中正常的细胞周期控制提供新的思路。
