MDM2 oncogene as a novel target for human cancer therapy

The MDM2 oncogene was first cloned as an amplified gene on a murine double- minute chromosome in the 3T3DM cell line, a spontaneously transformed deriv ative of BALB/c 3T3 cells. The MDM2 oncogene has now been shown to be ampli fied or overexpressed in many human cancers. It also has been suggested tha t MDM2 levels are associated with poor prognosis of several human cancers. The most exciting finding is the MDM2-p53 autoregulatory feedback loop that regulates the function of the p53 tumor suppressor gene. The MDM2 gene is a target for direct transcriptional activation by p53, and the MDM2 protein is a negative regulator of p53. The MDM2 oncoprotein binds to the p53 prot ein, inhibiting p53 functions as a transcription factor and inducing p53 de gradation. The p53 tumor suppressor has an important role in cancer therapy , with p53-mediated cell growth arrest and/or apoptosis being major mechani sms of action for many clinically used cancer chemotherapeutic agents and r adiation therapy. Therefore, the MDM2-p53 interaction may be a target for c ancer therapy. In addition, the negative regulation of p53 by MDM2 may limi t the magnitude of p53 activation by DNA damaging agents, thereby limiting their therapeutic effectiveness. If the MDM2 feed-back inhibition df p53 is interrupted, a significant increase in functional p53 levels will increase p53-mediated therapeutic effectiveness. Several approaches have now been t ested using this strategy, including polypeptides targeted to MDM2-p53 bind ing domain and antisense oligonucleotides that specifically inhibit MDM2 ex pression. In addition to the interaction with p53, the MDM2 protein has bee n found to have interactions with other cellular proteins such as pRb and E 2F-1. Although the exact function and significance of these interactions ar e not fully understood, the p53-independent functions of MDM2 may have a ro le in cancer etiology and progression, indicating that the MDM2 oncogene is a potential molecular target for cancer therapy.