title: Adenoviral E1A targets Mdm4 to stabilize tumor suppressor p53.
abstract: The adenoviral protein E1A associates with multiple anticancer activities, including stabilization of p53 tumor suppressor, and has been tested through gene therapy approaches in clinical trials. To identify potential E1A-binding proteins involved in E1A's anticancer activities, we screened a yeast two-hybrid library and identified Mdm4, an Mdm2-related p53-binding protein, as a novel E1A-binding protein. The NH(2)-terminal region of Mdm4 and the CR1 domain of E1A were required for the interaction between E1A and Mdm4. E1A preferentially bound to Mdm4 rather than Mdm2 and formed a complex with p53 in the presence of Mdm4, resulting in the stabilization of p53 in a p14(ARF)-independent manner. E1A failed to stabilize p53 in the absence of Mdm4, showing that Mdm4 was required for p53 stabilization by E1A. Moreover, E1A-mediated stabilization of p53 occurred in nucleus. Although it had no effect on the p53-Mdm2 interaction, E1A facilitated Mdm4 binding to p53 and inhibited Mdm2 binding to Mdm4, resulting in decreased nuclear exportation of p53. Thus, our findings highlighted a novel mechanism, whereby E1A stabilized the p53 tumor suppressor through Mdm4.
authors.affiliation: Department of Molecular, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Chi-Ping
authors.initials: CP
authors.lastname: Day
authors.forename: Jer-Yen
authors.initials: JY
authors.lastname: Yang
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Tsai
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
authors.forename: Hsiu-Ming
authors.initials: HM
authors.lastname: Shih
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D017500:Adenovirus E1A Proteins / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D017500:Adenovirus E1A Proteins; C461497:Mdm4 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases