p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53

The p53 tumour suppressor is frequently inactivated in human tumours, One f orm of inactivation results from overexpression of MDM2, that normally form s a negative auto-regulatory loop with p53 and inhibits its activity throug h complex formation, We have investigated whether disrupting the MDM2-p53 c omplex in cells that overexpress MDM2 is sufficient to trigger p53 mediated cell death. We find that expression of a peptide homologue of p53 that bin ds to MDM2 leads to increased p53 levels and transcriptional activity. The consequences are increased expression of the downstream effecters MDM2 and p21(WAF1/CIP1), inhibition of colony formation, cell cycle arrest and cell death. There is also a decrease in E2F activity, that might have been due t o the known physical and functional interactions of MDM2 with E2F1/DP1, How ever, this decrease is p53 dependent, as are also colony formation, cell cy cle arrest and cell death, These results show that a peptide homologue of p 53 is sufficient to induce p53 dependent cell death in cells overexpressing MDM2, and support the notion that disruption of the p53-MDM2 complex is a target for the development of therapeutic agents.