State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology and Graduate School, Chinese Academy of Sciences, Beijing 100101, China.
Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1720-5. doi: 10.1073/pnas.1211604110. Epub 2013 Jan 14.
Large numbers of studies have focused on the posttranslational regulation of p53 activity. One of the best-known negative regulators for p53 is MDM2, an E3 ubiquitin ligase that promotes p53 degradation through proteasome degradation pathways. Additional E3 ligases have also been reported to negatively regulate p53. However, whether these E3 ligases have distinct/overlapping roles in the regulation of p53 is largely unknown. In this study, we identify RNF2 (ring finger protein 2) as an E3 ligase that targets p53 for degradation. The E3 ligase activity of RNF2 requires Bmi1 protein, a component of the polycomb group (PcG) complex. The up-regulation of p53 does not affect RNF2 expression. Unlike Mdm2, RNF2 only degrades p53 in selective cell lines, such as those from germ-cell tumors. The knockdown of RNF2 induces apoptosis, which can be rescued through the reduction of p53 expression. Moreover, the down-regulation of RNF2 expression in germ-cell tumors significantly reduces tumor cell growth, while the simultaneous down-regulation of both genes restores tumor cell growth in vitro and in tumor xenograft models. Furthermore, a reverse correlation between RNF2 and p53 expression was detected in human ovarian cancer tissues. Together, these results indicate that RNF2 is an E3 ligase for p53 degradation in selective cells, implicating RNF2 as a therapeutic target to restore tumor suppression through p53 in certain tumor cells.
大量研究集中在 p53 活性的翻译后调控上。p53 的一个著名的负调控因子是 MDM2，它是一种 E3 泛素连接酶，通过蛋白酶体降解途径促进 p53 降解。此外，还有其他 E3 连接酶被报道可负调控 p53。然而，这些 E3 连接酶在 p53 调节中是否具有独特/重叠的作用尚不清楚。在这项研究中，我们确定 RNF2（环指蛋白 2）为一种 E3 连接酶，可靶向 p53 进行降解。RNF2 的 E3 连接酶活性需要 Bmi1 蛋白，它是多梳组（PcG）复合物的一个组成部分。p53 的上调并不影响 RNF2 的表达。与 Mdm2 不同，RNF2 仅在选择性细胞系（如生殖细胞肿瘤）中降解 p53。RNF2 的敲低诱导细胞凋亡，而通过降低 p53 的表达可以挽救这种凋亡。此外，生殖细胞肿瘤中 RNF2 表达的下调显著降低肿瘤细胞的生长，而同时下调这两个基因可在体外和肿瘤异种移植模型中恢复肿瘤细胞的生长。此外，在人类卵巢癌组织中检测到 RNF2 和 p53 表达之间存在反向相关性。总之，这些结果表明 RNF2 是一种选择性细胞中 p53 降解的 E3 连接酶，提示 RNF2 可作为通过 p53 在某些肿瘤细胞中恢复肿瘤抑制的治疗靶点。
