RESCUE OF EMBRYONIC LETHALITY IN MDM2-DEFICIENT MICE BY ABSENCE OF P53

THE Mdm2 proto-oncogene was originally identified as one of several ge nes contained on a mouse double minute chromosome present in a transfo rmed derivative of 3T3 cells(1). Overexpression of Mdm2 can immortaliz e primary cultures of rodent fibroblasts(2). Human MDM2 is amplified i n 30-40% of sarcomas, and is overexpressed in leukaemic cells(3,4). Th e Mdm2 oncoprotein forms a complex with the p53 tumour-suppressor prot ein and inhibits p53-mediated transregulation of gene expression(5,6) Because Mdm2 expression increases in response to p53, Mdm2-p53 binding may autoregulate Mdm2 expression and modulate the activity of p53 in the cell(7,8). We have created Mdm2-null and Mdm2/p53-null mice to det ermine whether Mdm2 possesses developmental functions in addition to t he ability to complex with p53, and to investigate the biological role of Mdm2-p53 complex formation in development. Mice deficient for Mdm2 die early in development. In contrast, mice deficient for both Mdm2 a nd p53 develop normally and are viable. These results suggest that a c ritical role of Mdm2 in development is the regulation of p53 function.