title: UBE4B promotes Hdm2-mediated degradation of the tumor suppressor p53.
abstract: The TP53 gene (encoding the p53 tumor suppressor) is rarely mutated, although frequently inactivated, in medulloblastoma and ependymoma. Recent work in mouse models showed that the loss of p53 accelerated the development of medulloblastoma. The mechanism underlying p53 inactivation in human brain tumors is not completely understood. We show that ubiquitination factor E4B (UBE4B), an E3 and E4 ubiquitin ligase, physically interacts with p53 and Hdm2 (also known as Mdm2 in mice). UBE4B promotes p53 polyubiquitination and degradation and inhibits p53-dependent transactivation and apoptosis. Notably, silencing UBE4B expression impairs xenotransplanted tumor growth in a p53-dependent manner and overexpression of UBE4B correlates with decreased expression of p53 in these tumors. We also show that UBE4B overexpression is often associated with amplification of its gene in human brain tumors. Our data indicate that amplification and overexpression of UBE4B represent previously undescribed molecular mechanisms of inactivation of p53 in brain tumors.
authors.affiliation: Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Scott L
authors.initials: SL
authors.lastname: Pomeroy
authors.forename: Manuel
authors.initials: M
authors.lastname: Ferreira
authors.forename: Natalia
authors.initials: N
authors.lastname: Teider
authors.forename: Juliana
authors.initials: J
authors.lastname: Mariani
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Shigetsugu
authors.initials: S
authors.lastname: Hatakeyama
authors.forename: Victor A
authors.initials: VA
authors.lastname: Tron
authors.forename: Linda F
authors.initials: LF
authors.lastname: Saltibus
authors.forename: Leo
authors.initials: L
authors.lastname: Spyracopoulos
authors.forename: Roger P
authors.initials: RP
authors.lastname: Leng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001932:Brain Neoplasms / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D041681:NIH 3T3 Cells; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases
chemical_list: D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D043743:Ubiquitin-Protein Ligase Complexes; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C473697:UBE4B protein, human; D044767:Ubiquitin-Protein Ligases