Cancer Research Institute, XiangYa School of Medicine, Central South University, Changsha, China.
Cell Cycle. 2012 Jun 15;11(12):2327-36. doi: 10.4161/cc.20771.
Disruption of the gatekeeper p53 tumor suppressor is involved in various virus-associated tumorigeneses, with aberrant ubiquitination as the major cause of p53 abnormalities in virus-associated tumors. Of note, wild-type p53 is accumulated in Epstein-Barr virus (EBV)-associated tumors, especially in nasopharyngeal carcinoma (NPC). We have previously identified that p53 is accumulated and phosphorylated by EBV oncoprotein latent membrane protein 1 (LMP1) in NPC. Here, we further found that LMP1 promoted p53 accumulation via two distinct ubiquitin modifications. LMP1 promoted p53 stability and accumulation by suppressing K48-linked ubiquitination of p53 mediated by E3 ligase MDM2, which is associated with its phosphorylation at Ser20, while increasing the levels of total cellular ubiquitinated p53. LMP1 also induced K63-linked ubiquitination of p53 by interacting with tumor necrosis factor receptor-associated factor 2 (TRAF2), thus contributing to p53 accumulation. Furthermore, LMP1 rescued tumor cell apoptosis and cell cycle arrest mediated by K63-linked ubiquitination of p53. Collectively, these results demonstrate aberrant ubiquitin modifications of p53 and its biological functions by viral protein LMP1, which has broad implications to the pathogenesis of multiple EBV-associated tumors.
破坏看门者 p53 肿瘤抑制因子与各种病毒相关的肿瘤发生有关，异常的泛素化是病毒相关肿瘤中 p53 异常的主要原因。值得注意的是，野生型 p53 在 Epstein-Barr 病毒（EBV）相关肿瘤中积累，特别是在鼻咽癌（NPC）中。我们之前已经确定 EBV 癌蛋白潜伏膜蛋白 1（LMP1）在 NPC 中积累和磷酸化 p53。在这里，我们进一步发现 LMP1 通过两种不同的泛素修饰促进 p53 的积累。LMP1 通过抑制 E3 连接酶 MDM2 介导的 p53 的 K48 连接泛素化来促进 p53 的稳定性和积累，这与 p53 在 Ser20 处的磷酸化有关，同时增加总细胞泛素化 p53 的水平。LMP1 还通过与肿瘤坏死因子受体相关因子 2（TRAF2）相互作用诱导 p53 的 K63 连接泛素化，从而有助于 p53 的积累。此外，LMP1 挽救了由 p53 的 K63 连接泛素化介导的肿瘤细胞凋亡和细胞周期停滞。总之，这些结果表明病毒蛋白 LMP1 导致 p53 的异常泛素修饰及其生物学功能，这对多种 EBV 相关肿瘤的发病机制具有广泛的意义。
