title: MDM2 and MDMX bind and stabilize the p53-related protein p73.
abstract: The p53 gene encodes one of the most important tumor suppressors in human cells and undergoes frequent mutational inactivation in cancers. MDM2, a transcriptional target of p53, binds p53 and can both inhibit p53-mediated transcription [1] [2] and target p53 for proteasome-mediated proteolysis [3] [4]. A close relative of p53, p73, has recently been identified [5] [6]. Here, we report that, like p53, p73alpha and the alternative transcription product p73beta also bind MDM2. Interaction between MDM2 and p53 represents a key step in the regulation of p53, as MDM2 promotes the degradation of p53. In striking contrast to p53, the half-life of p73 was found to be increased by binding to MDM2. Like MDM2, the MDM2-related protein MDMX also bound p73 and stabilized the level of p73. Moreover, the growth suppression functions of p73 and the induction of endogenous p21, a major mediator of the p53-dependent growth arrest pathway, were enhanced in the presence of MDM2. These differences between the regulation of p53 and p73 by MDM2/MDMX may highlight a physiological difference in their action.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, OX1 3QU, UK.
authors.forename: W M
authors.initials: WM
authors.lastname: Ongkeko
authors.forename: X Q
authors.initials: XQ
authors.lastname: Wang
authors.forename: W Y
authors.initials: WY
authors.lastname: Siu
authors.forename: A W
authors.initials: AW
authors.lastname: Lau
authors.forename: K
authors.initials: K
authors.lastname: Yamashita
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
authors.forename: L S
authors.initials: LS
authors.lastname: Cox
authors.forename: R Y
authors.initials: RY
authors.lastname: Poon
mesh_terms: D002455:Cell Division; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004355:Drug Stability; D016147:Genes, Tumor Suppressor; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2