title: UBE4B, a ubiquitin chain assembly factor, is required for MDM2-mediated p53 polyubiquitination and degradation.
abstract: Although MDM2 is known to be a critical negative regulator of p53, MDM2 only catalyzes p53 mono- or multiple monoubiquitination in vitro and in vivo, which is insufficient for the initiation of proteasomal degradation. MDM2 does not polyubiquitinate p53 in vitro, however, which indicates that the activity of other ubiquitin ligase(s) or cofactor(s) is required for MDM2-mediated p53 polyubiquitination and degradation. In our recent study, we demonstrated that UBE4B, an E3 and E4 ubiquitin ligase with a U-box domain, interacts physically with both p53 and MDM2. Our findings revealed that UBE4B negatively regulates the level of p53 and inhibits p53-dependent transactivation and apoptosis. We propose that inhibition of MDM2 binding to UBE4B may provide another approach to inhibit MDM2 E3 ligase activity for tumor suppressor p53. It could lead to novel anticancer therapies, with the possibility of reducing the public health burden from cancer.
authors.affiliation: Heritage Medical Research Centre, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Roger P
authors.initials: RP
authors.lastname: Leng
mesh_terms: D000818:Animals; D006801:Humans; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D043743:Ubiquitin-Protein Ligase Complexes / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination
chemical_list: D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D043743:Ubiquitin-Protein Ligase Complexes; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C473697:UBE4B protein, human; C471292:Ube4b protein, mouse; D044767:Ubiquitin-Protein Ligases