State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200433, People's Republic of China.
Mol Biol Rep. 2011 Jan;38(1):229-36. doi: 10.1007/s11033-010-0099-x. Epub 2010 Mar 24.
MDM2, Pirh2 and COP1 are important E3 ubiquitin ligases, which directly interact with p53 and target p53 for proteasome-mediated degradation. MDMX, the MDM2 homologous protein, inhibits p53-mediated transcription activity. The interplay between MDM2, MDMX, Pirh2 and COP1 has not been reported, except the interaction between MDM2 and MDMX. Here, we reported that there were interactions between these four proteins independently of p53. The protein levels of MDM2, MDMX, Pirh2 and COP1 changed when any two of them were co-transfected. Our data also showed that the integrity of MDM2 RING finger domain was crucial for its ability to elevate the protein levels of COP1 and Pirh2. Any two of these four proteins could inhibit p53-mediated transcriptional activity synergistically. Furthermore, COP1 inhibited MDM2 self-ubiquitination and interfered with MDMX ubiquitination by MDM2. Our results suggest that MDM2, MDMX, Pirh2 and COP1 might inhibit p53 activity synergistically in vivo.
MDM2、Pirh2 和 COP1 是重要的 E3 泛素连接酶，它们直接与 p53 相互作用，并将 p53 靶向蛋白酶体介导的降解。MDMX 是 MDM2 的同源蛋白，可抑制 p53 介导的转录活性。除了 MDM2 和 MDMX 之间的相互作用外，MDM2、MDMX、Pirh2 和 COP1 之间的相互作用尚未被报道。在这里，我们报道了这四种蛋白质之间存在相互作用，而与 p53 无关。当其中两种蛋白质共转染时，MDM2、MDMX、Pirh2 和 COP1 的蛋白水平发生变化。我们的数据还表明，MDM2 RING 指结构域的完整性对于其提高 COP1 和 Pirh2 蛋白水平的能力至关重要。这四种蛋白质中的任意两种都可以协同抑制 p53 介导的转录活性。此外，COP1 抑制 MDM2 自身泛素化，并干扰 MDM2 对 MDMX 的泛素化。我们的结果表明，MDM2、MDMX、Pirh2 和 COP1 可能在体内协同抑制 p53 活性。
