Adenoviral E1A targets Mdm4 to stabilize tumor suppressor p53.
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.
Li
Zheng
Z
Department of Molecular, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Day
Chi-Ping
CP
Yang
Jer-Yen
JY
Tsai
Wen-Bin
WB
Lozano
Guillermina
G
Shih
Hsiu-Ming
HM
Hung
Mien-Chie
MC
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
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