title: Casein kinase 1α regulates an MDMX intramolecular interaction to stimulate p53 binding.
abstract: MDMX is an important regulator of p53 during embryonic development and malignant transformation. Previous studies showed that casein kinase 1α (CK1α) stably associates with MDMX, stimulates MDMX-p53 binding, and cooperates with MDMX to inactivate p53. However, the mechanism by which CK1α stimulates MDMX-p53 interaction remains unknown. Here, we present evidence that p53 binding by the MDMX N-terminal domain is inhibited by the central acidic region through an intramolecular interaction that competes for the p53 binding pocket. CK1α binding to the MDMX central domain and phosphorylation of S289 disrupts the intramolecular interaction, allowing the N terminus to bind p53 with increased affinity. After DNA damage, the MDMX-CK1α complex is disrupted by Chk2-mediated phosphorylation of MDMX at S367, leading to reduced MDMX-p53 binding. Therefore, CK1α is an important functional partner of MDMX. DNA damage activates p53 in part by disrupting CK1α-MDMX interaction and reducing MDMX-p53 binding affinity.
authors.affiliation: Molecular Oncology Department, Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Shaofang
authors.initials: S
authors.lastname: Wu
authors.forename: Lihong
authors.initials: L
authors.lastname: Chen
authors.forename: Andreas
authors.initials: A
authors.lastname: Becker
authors.forename: Ernst
authors.initials: E
authors.lastname: Schonbrunn
authors.forename: Jiandong
authors.initials: J
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D048128:Casein Kinase Ialpha / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D048128:Casein Kinase Ialpha