title: Interaction of regulators Mdm2 and Mdmx with transcription factors p53, p63 and p73.
abstract: The negative regulation of p53, a major human tumor suppressor, by Mdm2 and Mdmx is crucial for the survival of a cell, whereas its aberrant function is a common feature of cancer.  Both Mdm proteins act through the spatial occlusion of the p53 transactivation (TA) domain and by the ubiquitination of p53, resulting in its degradation.  Two p53 homologues, p63 and p73, have been described in humans.  Unlike p53, these proteins regulate developmental processes rather than genome stability.  Both p63 and p73 contain TA domains homologous to that of p53, but relatively little is known about their regulation by Mdm2 or Mdmx.  Here, we present a detailed characterization of the interaction of Mdm2 and Mdmx with the TA domains of p63 and p73. Earlier reports of Mdm2 and Mdmx interactions with p73 are substantiated by the detailed quantitative characterization reported in this study. Most importantly, earlier contradictions concerning the presumed interaction of the Mdm proteins with p63 are convincingly resolved and for the first time, the affinities of these interactions are determined.  Finally, the contribution of these findings to our understanding of the physiological role of these interactions is discussed.
authors.affiliation: Department of Microbiology, Faculty of Biochemistry, Jagiellonian University, Krakow, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Zdzalik
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Pustelny
authors.forename: Sylwia
authors.initials: S
authors.lastname: Kedracka-Krok
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Huben
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Pecak
authors.forename: Benedykt
authors.initials: B
authors.lastname: Wladyka
authors.forename: Stefan
authors.initials: S
authors.lastname: Jankowski
authors.forename: Adam
authors.initials: A
authors.lastname: Dubin
authors.forename: Jan
authors.initials: J
authors.lastname: Potempa
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Dubin
mesh_terms: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors; D014364:Tryptophan / Q000737:chemistry; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C115051:TP63 protein, human; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014364:Tryptophan; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2