title: The anaphase-promoting complex/cyclosome is an E3 ubiquitin ligase for Mdm2.
abstract: The Mdm2 proto-oncoprotein is the primary negative regulator for p53. While it is believed that Mdm2 degradation is regulated via its own E3 ubiquitin ligase activity, recent development of knock-in mouse models demonstrates that Mdm2 E3 ligase function is dispensable for self-degradation in vivo. Here, we show that the anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase for Mdm2 degradation. We demonstrate that APC2, a scaffold subunit of APC/C, binds to Mdm2 and is required for Mdm2 polyubiquitination and proteasomal degradation. Downregulation of APC2 by RNAi results in transcription-independent accumulation of Mdm2 and attenuation of stress-induced p53 stabilization, leading to decreased senescence and increased cell survival. Furthermore, APC2 expression is frequently downregulated in human cancers; in tumor cell lines, APC2 downregulation correlates with Mdm2 overexpression. Our study shows the regulation of Mdm2 by the E3 ubiquitin ligase APC/C and has important therapeutic implications for tumors with Mdm2 overexpression.
authors.affiliation: Department of Radiation Oncology; School of Medicine; University of North Carolina at Chapel Hill; Chapel Hill, NC USA; Lineberger Comprehensive Cancer Center; School of Medicine; University of North Carolina at Chapel Hill; Chapel Hill, NC USA; Curriculum in Genetics and Molecular Biology; School of Medicine; University of North Carolina at Chapel Hill; Chapel Hill, NC USA.
authors.forename: Yizhou
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Radiation Oncology; School of Medicine; University of North Carolina at Chapel Hill; Chapel Hill, NC USA; Lineberger Comprehensive Cancer Center; School of Medicine; University of North Carolina at Chapel Hill; Chapel Hill, NC USA; Curriculum in Genetics and Molecular Biology; School of Medicine; University of North Carolina at Chapel Hill; Chapel Hill, NC USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Tollini
authors.affiliation: Department of Radiation Oncology; School of Medicine; University of North Carolina at Chapel Hill; Chapel Hill, NC USA; Lineberger Comprehensive Cancer Center; School of Medicine; University of North Carolina at Chapel Hill; Chapel Hill, NC USA.
authors.forename: Tae-Hyung
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Department of Radiation Oncology; School of Medicine; University of North Carolina at Chapel Hill; Chapel Hill, NC USA; Lineberger Comprehensive Cancer Center; School of Medicine; University of North Carolina at Chapel Hill; Chapel Hill, NC USA.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Itahana
authors.affiliation: Department of Radiation Oncology; School of Medicine; University of North Carolina at Chapel Hill; Chapel Hill, NC USA; Lineberger Comprehensive Cancer Center; School of Medicine; University of North Carolina at Chapel Hill; Chapel Hill, NC USA; Department of Pharmacology; School of Medicine; University of North Carolina at Chapel Hill; Chapel Hill, NC USA; Laboratory of Biological Cancer Therapy; Xuzhou Medical College; Xuzhou, China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D064190:Apc2 Subunit, Anaphase-Promoting Complex-Cyclosome / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008822:Mice, Transgenic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D016159:Tumor Suppressor Protein p53; D064190:Apc2 Subunit, Anaphase-Promoting Complex-Cyclosome; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: APC/C; E3; Mdm2; p53; ubiquitin