Chen Lihong, Chen Jiandong
Molecular Oncology Program, H Lee Moffitt Comprehensive Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Oncogene. 2003 Aug 14;22(34):5348-57. doi: 10.1038/sj.onc.1206851.
The p53 tumor suppressor is regulated by MDM2-mediated ubiquitination and degradation. Ubiquitination of p53 is regulated by ARF, which binds to MDM2 and inhibits its E3 ligase function. P53 is also subjected to modification by conjugation of SUMO-1. We found that a p53 mutant deficient for MDM2 binding (p53(14Q19S)) is poorly sumoylated in vivo compared to wild-type p53. Overexpression of MDM2 increases the level of p53 sumoylation, which is further stimulated by expression of ARF. Stimulation of p53 sumoylation requires a highly conserved region (102-116) encoded by exon 2 of ARF and correlates with the ability of ARF to target p53 to the nucleolus. An MDM2 deletion mutant (MDM2(Delta222-437)) with activated cryptic nucleolar localization signal also targets p53 to the nucleolus and efficiently promotes p53 sumoylation in the absence of ARF. Direct targeting of p53 to the nucleolus enhances its sumoylation in an MDM2- and ARF-dependent fashion. These results show that p53 sumoylation is regulated by MDM2- and ARF-mediated nucleolar targeting.
p53肿瘤抑制因子受MDM2介导的泛素化和降解作用调控。p53的泛素化受ARF调节，ARF与MDM2结合并抑制其E3连接酶功能。p53还会发生SUMO-1缀合修饰。我们发现，与野生型p53相比，一种缺乏MDM2结合能力的p53突变体（p53(14Q19S)）在体内的SUMO化水平较低。MDM2的过表达会增加p53的SUMO化水平，ARF的表达会进一步刺激这种增加。p53 SUMO化的刺激需要ARF外显子2编码的一个高度保守区域（102 - 116），并且与ARF将p53靶向核仁的能力相关。一种具有激活的隐匿性核仁定位信号的MDM2缺失突变体（MDM2(Delta222 - 437)）也能将p53靶向核仁，并在没有ARF的情况下有效促进p53的SUMO化。将p53直接靶向核仁以MDM2和ARF依赖的方式增强其SUMO化。这些结果表明，p53的SUMO化受MDM2和ARF介导的核仁靶向作用调控。
