The protein human homologue of mouse double minute 2 (MDM2) was first identified as the product of the MDM2 gene amplified in transformed murine cells. It is a p53-binding nuclear protein that antagonizes and downregulates p53 activity. The gene maps to 12q14–q15 and is amplified in certain human tumors, including sarcomas, glioblastomas, and astrocytomas.
Discovery and Significance
MDM2 was discovered by Donna George’s laboratory as a gene that is amplified within double-minute chromosomes in 3T3DM cells and encodes a cellular transforming activity that promotes tumorigenicity in xenografts. Its association with p53 was first observed in immunoprecipitation analyses of p53 as a coprecipitating protein migrating with an apparent molecular weight of 95 kDa. Subsequently, it was shown that overexpression of MDM2 leads to increased degradation of p53 via the proteasome, thereby establishing its role as a crucial regulator of p53 levels.