Abstract 613: Depletion of Mdm2 and Mdm4 by adenovirus: Molecular mechanism and anticancer therapeutic implication

Abstract

Abstract Mdm2 and Mdm4 are two paralogous proteins. They contain a conserved p53-binding domain in the N-terminal region and a RING-finger domain in the C-terminal part. Both proteins physically bind p53 and prevent p53 activation. Biochemically, Mdm2 acts as an E3 ubiquitin ligase of p53 and promotes ubiquitin-dependent p53 degradation. Mdm4 does not appear to have intrinsic E3 ubiquitin ligase activity and may negatively control p53 function through suppressing p53-mediated transactivation of gene expression. Mdm2 and Mdm4 also form heterodimer, which suggests that Mdm2 and Mdm4 might cooperatively control p53 activity. In vivo, both Mdm2 and Mdm4 have an essential but non-redundant function in suppressing p53 activity to enable embryonic development. Mdm2 and Mdm4 are overexpressed in several types of human cancer such as breast cancer and osteosarcoma. In transgenic mouse models, overexpression of Mdm2 or Mdm4 leads to tumorigenesis. Thus, both Mdm2 and Mdm4 are bona fide oncogenes. Several small molecules that disrupt the interaction between p53 and Mdm2 and Mdm4 have been shown to induce p53 activation, cell cycle arrest and apoptosis. These compounds also cause tumor repression in preclinical animal models. Thus, they have clinical potentials for treating various types of human cancer. Biological agents that specifically target Mdm2 and Mdm4 have not been described. We found that adenovirus infection of diverse type of cancer cells results in dramatic downregulation of both Mdm2 and Mdm4. Adenovirus E1B-55K binds specifically both Mdm2 and Mdm4 in cells and in vitro, demonstrating specific interactions between E1B-55K and Mdm2 or Mdm4. Cotransfection experiments indicated that E1B 55K alone was sufficient to deplete Mdm2 and Mdm4. E1B-55K is known to form a functional E3 ubiquitin ligase consisting of Cul2 or Cul5. Thus, it is likely that E1B-55K targets Mdm2 and Mdm4 for ubiquitin-mediated proteosomal degradation. Based on these observations, we hypothesize that adenovirus is effective for treating cancers with overexpression of Mdm2 or Mdm4. We are currently testing whether adenoviral therapy is efficacious on treating such cancers in cell culture and animal models. (This work was supported by Bankhead-Coley Cancer Research Program of the Florida Department of Health.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 613. doi:10.1158/1538-7445.AM2011-613