title: RNF2/Ring1b negatively regulates p53 expression in selective cancer cell types to promote tumor development.
abstract: 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.
authors: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology and Graduate School,  Chinese Academy of Sciences, Beijing 100101,  China.
authors: Wen-jing
authors: WJ
authors: Su
authors: Jun-shun
authors: JS
authors: Fang
authors: Feng
authors: F
authors: Cheng
authors: Chao
authors: C
authors: Liu
authors: Fang
authors: F
authors: Zhou
authors: Jian
authors: J
authors: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D047368:Tumor Burden / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D063150:Polycomb Repressive Complex 1; C489841:RNF2 protein, human; D044767:Ubiquitin-Protein Ligases