INTERACTION BETWEEN THE RETINOBLASTOMA PROTEIN AND THE ONCOPROTEIN MDM2

INACTIVATION of tumour-suppressor genes leads to deregulated cell prol iferation and is a key factor in human tumorigenesis. Both p53 and ret inoblastoma genes are frequently mutated in human cancers(1,2), and th e simultaneous inactivation of RB and p53 is frequently observed in a variety of naturally occurring human tumours(3). Furthermore, three di stinct DNA tumour virus groups papovaviruses, adenoviruses and human p apillomaviruses-transform cells by targeting and inactivating certain functions of both the p53 and retinoblastoma proteins(1,2). The cellul ar oncoprotein, Mdm2, binds to and downmodulates p53 function(4-6); it s human homologue, MDM2, is amplified in certain human tumours, includ ing sarcomas(7-9) and gliomas(10). Overproduction of Mdm2 is both tumo rigenic(4) and capable of immortalizing primary rat embryo fibroblasts (11). Here we show that MDM2 interacts physically and functionally wit h pRB and, as with p53, inhibits pRB growth regulatory function. There fore, both pRB and p53 can be subjected to negative regulation by the product of a single cellular proto-oncogene.