Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis

The Mdm2 proto-oncogene is amplified to high copy numbers in human sarcomas and is overexpressed in a wide variety of other human cancers. Because Mdm 2 protein forms a complex with the p53 tumor suppressor protein and down-re gulates p53 function, the oncogenic potential of Mdm2 is presumed to be p53 -dependent. To model these conditions in mice, we have used the entire Mdm2 gene, under transcriptional control of its native promoter region, as a tr ansgene to create mice that overexpress Mdm2. The transgenic mice are predi sposed to spontaneous tumor formation, and the incidence of sarcomas observ ed in the Mdm2-transgenic mice in the presence or absence of functional p53 demonstrates that, in addition to Mdm2-mediated inactivation of p53, there exists a p53-independent role for Mdm2 in tumorigenesis.