title: RNF12 promotes p53-dependent cell growth suppression and apoptosis by targeting MDM2 for destruction.
abstract: The oncoprotein MDM2 is an E3 ubiquitin ligase that targets tumor suppressor p53 for ubiquitination and proteasomal degradation, restraining the potent activity of p53 and enabling cell survival and proliferation. Dysregulation of MDM2-p53 axis was frequently observed in human cancers. Originally, it is proposed that MDM2 degradation was mainly achieved by destructive self-ubiquitination. However, recent study suggests that MDM2 may be targeted for degradation by an external E3 ubiquitin ligase(s) under physiological levels. Here, we identified E3 ubiquitin ligase RNF12 as an MDM2-interacting protein through yeast two hybrid methods. We demonstrated that RNF12 targets MDM2 for ubiquitination and proteasomal-dependent degradation, which is independent of MDM2's self-ubiquitination activity. Accordingly, RNF12 elevates p53 protein level by abrogating MDM2-mediated p53 degradation and ubiquitination. Finally, we showed that RNF12 regulates cell growth suppression and DNA damage-induced apoptosis in a p53-dependent manner. Taken together, we establish RNF12 as a novel positive regulator of p53 pathway and an external E3 ubiquitin ligase for MDM2 destruction. These data shed light on the potential roles of RNF12 in MDM2-p53 axis and tumor suppression.
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai 200433, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai 200433, China.
authors.forename: Chenji
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai 200433, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China.
authors.forename: Jiantao
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China.
authors.forename: Enceng
authors.initials: E
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai 200433, China.
authors.forename: Xianmei
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, Jiangxi Institute of Gastroenterology & Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China.
authors.forename: Dejie
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai 200433, China. Electronic address: longyu@fudan.edu.cn.
authors.forename: Long
authors.initials: L
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai 200433, China; Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China. Electronic address: pzzhang@fudan.edu.cn.
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Zhang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C492370:RLIM protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Apoptosis; Degradation; MDM2; RNF12; Ubiquitination; p53