title: UBE4B targets phosphorylated p53 at serines 15 and 392 for degradation.
abstract: Phosphorylation of p53 is a key mechanism responsible for the activation of its tumor suppressor functions in response to various stresses. In unstressed cells, p53 is rapidly turned over and is maintained at a low basal level. After DNA damage or other forms of cellular stress, the p53 level increases, and the protein becomes metabolically stable. However, the mechanism of phosphorylated p53 regulation is unclear. In this study, we studied the kinetics of UBE4B, Hdm2, Pirh2, Cop1 and CHIP induction in response to p53 activation. We show that UBE4B coimmunoprecipitates with phosphorylated p53 at serines 15 and 392. Notably, the affinity between UBE4B and Hdm2 is greatly decreased after DNA damage. Furthermore, we observe that UBE4B promotes endogenous phospho-p53(S15) and phospho-p53(S392) degradation in response to IR. We demonstrate that UBE4B and Hdm2 repress p53S15A, p53S392A, and p53-2A(S15A, S392A) functions, including p53-dependent transactivation and growth inhibition. Overall, our results reveal that UBE4B plays an important role in regulating phosphorylated p53 following DNA damage.
authors.affiliation: Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors.forename: Cheng
authors.initials: C
authors.lastname: Du
authors.affiliation: Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors.forename: Roger P
authors.initials: RP
authors.lastname: Leng
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D004789:Enzyme Activation; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D010766:Phosphorylation; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination / Q000502:physiology
chemical_list: C495901:TP53 protein, human; 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
keywords: E3 ligases; p53; phosphorylation; ubiquitination