Abstract
Abstract The activity of the p53 tumor suppressor is regulated by multiple factors. Two of these, Mdm2 and Mdm4, function as p53 inhibitors in vivo in multiple cell types. Loss of Mdm2 or Mdm4 in mice leads to embryo and cell lethal phenotypes that are rescued by deletion of p53. Additionally, haplo insufficiency at these loci results in elevated p53 activity, delayed lymphomagenesis, and developmental defects in some cases. On the other hand, over expression of Mdm2 and Mdm4 occurs in many tumors most of which retain wild type p53. Mdm2 and Mdm4 transgenic mice are tumor prone. Additionally, a single nucleotide polymorphism (SNP) in the human MDM2 promoter increases the levels of MDM2 expression is associated with increased cancer risk. A mouse model with this SNP shows increased Mdm2 levels, decreased p53 activity, and an enhanced tumor phenotype. These data emphasize the exquisite sensitivity of the p53 pathway to changes in Mdm2 and Mdm4 gene dosage, and the consequences of those effects on development and tumorigenesis. Citation Format: Guillermina Lozano. The Mdm2/Mdm4 complex: A rheostat for p53 activity [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY29-02
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