title: Ubiquitin-specific peptidase 48 regulates Mdm2 protein levels independent of its deubiquitinase activity.
abstract: The overexpression of Mdm2 has been linked to the loss of p53 tumour suppressor activity in several human cancers. Here, we present results suggesting that ubiquitin-specific peptidase 48 (USP48), a deubiquitinase that has been linked in previous reports to the NF-κB signaling pathway, is a novel Mdm2 binding partner that promotes Mdm2 stability and enhances Mdm2-mediated p53 ubiquitination and degradation. In contrast to other deubiquitinating enzymes (DUBs) that have been previously implicated in the regulation of Mdm2 protein stability, USP48 did not induce Mdm2 stabilization by significantly reducing Mdm2 ubiquitination levels. Moreover, two previously characterized USP48 mutants lacking deubiquitinase activity were also capable of efficiently stabilizing Mdm2, indicating that USP48 utilizes a non-canonical, deubiquitination-independent mechanism to promote Mdm2 oncoprotein stability. This study represents, to the best of our knowledge, the first report suggesting DUB-mediated target protein stabilization that is independent of its deubiquitinase activity. In addition, our results suggest that USP48 might represent a new mechanism of crosstalk between the NF-κB and p53 stress response pathways.
authors.affiliation: Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.|International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Cetkovská
authors.affiliation: Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Šustová
authors.affiliation: Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.|International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
authors.forename: Stjepan
authors.initials: S
authors.lastname: Uldrijan
mesh_terms: D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C579215:USP48 protein, human; D064570:Ubiquitin-Specific Proteases