Rescue of Mdm4-deficient mice by Mdm2 reveals functional overlap of Mdm2 and Mdm4 in development
Graduate School of Biomedical Sciences; Department of Cell Biology; Department of Cancer Biology
Medical Subject Headings
Animals; Animals, Genetically Modified; Apoptosis; Cell Culture Techniques; Cell Proliferation; Cell Transformation, Neoplastic; Fibroblasts; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; *Genes, p53; Humans; Mice; Mice, Knockout; Nuclear Proteins; Phenotype; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Sarcoma
Life Sciences | Medicine and Health Sciences
The Mdm2 and Mdm4 genes are amplified and overexpressed in a variety of human cancers and encode structurally related oncoproteins that bind to the p53 tumor suppressor protein and inhibit p53 activity. Mice deleted for either Mdm2 or Mdm4 die during embryogenesis, and the developmental lethality of either mouse model can be rescued by concomitant deletion of p53. However, the phenotypes of Mdm2 and Mdm4-deficient mice suggest that Mdm2 and Mdm4 play nonoverlapping roles in regulating p53 activity during development, with Mdm2 regulating p53-mediated cell death and Mdm4 regulating p53-mediated inhibition of cell growth. Here, we describe complete rescue of Mdm4-deficient mice by expression of an Mdm2 transgene, and demonstrate that Mdm2 can regulate both p53-mediated apoptosis and inhibition of cell growth in the absence of Mdm4 in primary cells. Furthermore, deletion of Mdm4 enhances the ability of Mdm2 to promote cell growth and tumor formation, indicating that Mdm4 has antioncogenic properties when Mdm2 is overexpressed.
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Citation: Oncogene. 2005 Nov 24;24(53):7935-40. Link to article on publisher's site