title: MDM2 mediates p73 ubiquitination: a new molecular mechanism for suppression of p73 function.
abstract: The protein p73, a homologue of the tumor suppressor protein p53, is capable of inducing apoptosis and cell cycle arrest. MDM2 is transcriptionally activated by p73 and represses the functions of p73, including p73-dependent transactivation and growth suppression. However, the molecular mechanism of this repression is unknown. In this study, we show that MDM2 mediates p73 ubiquitination. MDM2 mainly utilizes K11, K29 and K63-linked chains to mediate p73 ubiquitination in vivo and in vitro. However, MDM2 is unable to promote p73 degradation in most tested cell lines. Surprisingly, we observe that overexpression of Mdm2 promotes p73 degradation mainly through Itch in Mdm2-null MEFs. We further find that Itch interacts with the transfected Mdm2 in Mdm2-null cells. Moreover, our findings reveal that the E3 ligase activity of MDM2 is required to repress p73-dependent apoptosis and cell cycle arrest but not p73-dependent transcriptional activity. Furthermore, the data suggest a link between p73 ubiquitination/MDM2 E3 ligase activity and p73 biological functions.
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Roger P
authors.initials: RP
authors.lastname: Leng
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D059447:Cell Cycle Checkpoints / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C432966:ITCH protein, human; C471637:Itch protein, mouse; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases
keywords: oncogene; protein degradation; tumor suppressor; ubiquitin E3 ligase; ubiquitination