Interaction between the retinoblastoma protein and the oncoprotein MDM2

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Abstract
INACTIVATION of tumour-suppressor genes leads to deregulated cell proliferation and is a key factor in human tumorigenesis. Both p53 and retinoblastoma genes are frequently mutated in human cancers1,2, and the simultaneous inactivation of RB andp53 is frequently observed in a variety of naturally occurring human tumours3. Furthermore, three distinct DNA tumour virus groups-papovaviruses, adenoviruses and human papillomaviruses-transform cells by targeting and inactivating certain functions of both the p53 and retinoblastoma proteins1,2. The cellular oncoprotein, Mdm2, binds to and downmodulates p53 function4–6; its human homologue, MDM2, is amplified in certain human tumours, including sarcomas7–9 and gliomas10. Overproduction of Mdm2 is both tumorigenic4 and capable of immortalizing primary rat embryo fibroblasts11. Here we show that MDM2 interacts physically and functionally with pRB and, as with p53, inhibits pRB growth regulatory function. Therefore, both pRB and p53 can be subjected to negative regulation by the product of a single cellular proto-oncogene.