Functions of the MDM2 oncoprotein

The p53 protein is activated in response to physiological stress resulting in either a G1 arrest of cells or apoptosis. As such, p53 must be tightly r egulated, and the MDM2 oncoprotein plays a central role in that regulatory process. The transcription of the Mdm2 oncogene is induced by the p53 prote in after DNA damage, and the MDM2 protein then binds to p53 and blocks its activities as a tumour suppressor and promotes its degradation. These two p roteins thus form an autoregulatory feedback loop in which p53 positively r egulates MDM2 levels and MDM2 negatively regulates p53 levels and activity. Immediately after ultraviolet (UV) irradiation MDM2 messenger RNA and prot ein levels fall in a p53-independent fashion, resulting in increased p53 le vels, The p53 protein is then activated as a transcription factor by posttr anslational modification permitting p53 to initiate its cell-cycle arrest o r apoptotic (programmed cell death) functions. At later times, after the re pair of DNA, MDM2 levels increase in a p53-dependent fashion. This inductio n of MDM2 results in the inhibition of p53 transcriptional activity and the degradation of p53 protein. MDM2-p53 complexes in the nucleus are transpor ted to the cytoplasm via signals present in the MDM2 protein, where p53 is degraded in the proteasome. Thus MDM2 acts as a nuclear-cytoplasmic shuttle for the p53 protein. There are many levels at which this process is regula ted, and as such there are many places for chemotherapeutic interventions. The amino-terminal domain of the MDM2 protein is all that is required to bi nd the p53 protein. The MDM2 protein has additional domains and therefore m ay have additional functions. Any of these MDM2 domains may contribute to M DM2's activities as an oncogene independent of its inhibition of the tumour suppressor functions of p53. Thus MDM2 itself could be a target for cancer therapeutic intervention.