REGULATION OF TRANSCRIPTION FUNCTIONS OF THE P53 TUMOR-SUPPRESSOR BY THE MDM-2 ONCOGENE

Background: Mdm-2, a zinc finger protein, negatively regulates the p53 tumor suppressor gene product by binding to it and preventing transcr iptional activation (16). Materials and Methods: Assays for p53 mediat ed transcription, repression and activation by mutant and wild-type p5 3 proteins were used to measure the ability of mdm-2 to block each act ivity. Results: Mdm-2 was able to inhibit all three functions of the w ild-type and mutant p53 activities; transcriptional activation by the wild-type protein, transcriptional activation by the mutant p53 protei n, and repression by the wild-type protein. Conclusions: The mdm prote in binds to the amino terminal portion of the p53 protein and, in so d oing, blocks the ability of p53 to interact with the transcriptional m achinery of the cell (23). The mdm-2 protein binds to both leucine-try ptophan residues at amino acids 22 and 23, from the amino terminal end of the protein, and in so doing, prevents all p53 functions. The abil ity of a mutant p53 protein to transactivate a multidrug resistance-1 gene promoter is blocked by mdm-2 and the ability of the wild-type p53 protein to repress transcription of some genes is also blocked by the mdm-2 protein. Thus, all three functions of the p53 protein-transcrip tional activation, repression and mutant protein activation-require th e p53 amino terminal domain functions and are regulated by the mdm-2 p rotein in a cell. When mdm-2 is overproduced, resulting in a tumor or transformation of a cell, all of the p53 activities are inactivated.