School of Life Sciences, Tsinghua University, Beijing 100842, China.
J Biol Chem. 2010 Jul 23;285(30):22818-30. doi: 10.1074/jbc.M110.126920. Epub 2010 May 18.
The tumor suppressor p53 protein is tightly regulated by a ubiquitin-proteasomal degradation mechanism. Several E3 ubiquitin ligases, including MDM2 (mouse double minute 2), have been reported to play an essential role in the regulation of p53 stability. However, it remains unclear how the activity of these E3 ligases is regulated. Here, we show that the HECT-type E3 ligase Smurf1/2 (Smad ubiquitylation regulatory factor 1/2) promotes p53 degradation by enhancing the activity of the E3 ligase MDM2. We provide evidence that the role of Smurf1/2 on the p53 stability is not dependent on the E3 activity of Smurf1/2 but rather is dependent on the activity of MDM2. We find that Smurf1/2 stabilizes MDM2 by enhancing the heterodimerization of MDM2 with MDMX, during which Smurf1/2 interacts with MDM2 and MDMX. We finally provide evidence that Smurf1/2 regulates apoptosis through p53. To our knowledge, this is the first report to demonstrate that Smurf1/2 functions as a factor to stabilize MDM2 protein rather than as a direct E3 ligase in regulation of p53 degradation.
肿瘤抑制因子 p53 蛋白受到泛素-蛋白酶体降解机制的严格调控。已有报道称，包括 MDM2（鼠双微体 2）在内的几种 E3 泛素连接酶在调节 p53 稳定性方面发挥着重要作用。然而，这些 E3 连接酶的活性如何被调控仍不清楚。在这里，我们发现 HECT 型 E3 连接酶 Smurf1/2（Smad 泛素化调节因子 1/2）通过增强 E3 连接酶 MDM2 的活性来促进 p53 的降解。我们提供的证据表明，Smurf1/2 对 p53 稳定性的作用不依赖于 Smurf1/2 的 E3 活性，而是依赖于 MDM2 的活性。我们发现 Smurf1/2 通过增强 MDM2 与 MDMX 的异二聚化来稳定 MDM2，在此过程中 Smurf1/2 与 MDM2 和 MDMX 相互作用。我们最终提供的证据表明 Smurf1/2 通过 p53 来调节细胞凋亡。据我们所知，这是首次报道表明 Smurf1/2 作为一种稳定 MDM2 蛋白的因子发挥作用，而不是作为调节 p53 降解的直接 E3 连接酶。
