Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, South Korea.
Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, South Korea.
Biochem Biophys Res Commun. 2021 Mar 5;543:23-28. doi: 10.1016/j.bbrc.2021.01.074. Epub 2021 Jan 24.
Downregulation of the p53 tumor suppressor in cancers is frequently accompanied by the upregulation of Wip1 (a phosphatase) and Mdm2 (an E3 ubiquitin ligase). Mdm2 binds and ubiquitinates p53, promoting its degradation by the proteasome. As the p53/Mdm2 interaction is alleviated by the phosphorylation of the serine-15 (S15) residue of p53, Wip1, which can directly dephosphorylate phospho-S15, facilitates the Mdm2-mediated degradation of p53. Here, we found that p21, previously shown to bind p53 and Mdm2, reduces the cellular levels of p53 protein by decreasing its stability. This is accompanied by a decrease in p53-S15 phosphorylation levels. In agreement, p21 promotes the p53/Wip1 interaction. Additionally, p21 interacts with Wip1, forming a trimeric complex of p53, p21, and Wip1. Studies using a p21 deletion mutant that cannot bind p53 revealed that the p53/p21 complex is more efficient than p53 alone in facilitating the binding of p53 to Wip1 and Mdm2. These findings indicate that p21 is a novel negative regulator of p53 stability and therefore, may be used as a target to restore p53 activity by preventing the action of Wip1 and Mdm2 on p53.
p53 肿瘤抑制因子在癌症中的下调通常伴随着 Wip1（一种磷酸酶）和 Mdm2（一种 E3 泛素连接酶）的上调。Mdm2 结合并泛素化 p53，促进其被蛋白酶体降解。由于 p53/Mdm2 相互作用被 p53 丝氨酸-15（S15）残基的磷酸化缓解，Wip1 可以直接去磷酸化磷酸化 S15，促进 Mdm2 介导的 p53 降解。在这里，我们发现先前显示与 p53 和 Mdm2 结合的 p21 通过降低其稳定性来降低细胞内 p53 蛋白水平。这伴随着 p53-S15 磷酸化水平的降低。一致地，p21 促进了 p53/Wip1 相互作用。此外，p21 与 Wip1 相互作用，形成 p53、p21 和 Wip1 的三聚体复合物。使用不能结合 p53 的 p21 缺失突变体进行的研究表明，p53/p21 复合物比单独的 p53 更有效地促进 p53 与 Wip1 和 Mdm2 的结合。这些发现表明 p21 是 p53 稳定性的新型负调节剂，因此，可用于通过防止 Wip1 和 Mdm2 对 p53 的作用来恢复 p53 活性。
