title: Phosphorylation of the acidic domain of Mdm2 by protein kinase CK2.
abstract: The Murine double-minute clone 2 (Mdm2) onco-protein is the principal regulator of the tumour suppressor, p53. Mdm2 acts as an E3-type ubiquitin ligase that mediates the ubiquitylation and turnover of p53 under normal, unstressed circumstances. In response to cellular stress, such as DNA damage, the Mdm2-p53 interaction is disrupted. Part of the mechanism of uncoupling p53 from Mdm2-mediated degradation involves hypo-phosphorylation of a cluster of phosphorylated serine residues in the central acidic domain of Mdm2. Here, we show that two of the residues within this domain that are phosphorylated in vivo, Ser-260 and Ser-269, are phosphorylated by CK2 in vitro. Treatment of cells with the CK2 inhibitor, 4,5,6,7-tetrabromo-2-azabenzimidazole (TBB), leads to the induction of p53 and downstream targets of p53 including Mdm2 itself and p21. These data are consistent with the idea that CK2-mediated phosphorylation of Mdm2 may regulate Mdm2-mediated p53 turnover.
authors.affiliation: Molecular Signalling Group, Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
authors.forename: Nerea
authors.initials: N
authors.lastname: Allende-Vega
authors.forename: Sylvia
authors.initials: S
authors.lastname: Dias
authors.forename: Diane
authors.initials: D
authors.lastname: Milne
authors.forename: David
authors.initials: D
authors.lastname: Meek
mesh_terms: D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014230:Triazoles / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: C103118:4,5,6,7-tetrabromo-2-azabenzimidazole; D011993:Recombinant Fusion Proteins; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D012694:Serine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D047390:Casein Kinase II