Stabilization of MDM2 by mutant p53

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DESCRIPTION: (provided by applicant) Nearly 50 percent of human tumors contain p53 point mutations in the DNA-binding core domain, which often cause overexpression of p53 due to stabilization. Certain p53 conformational mutants may also promote transformation by gain of function. Elucidating the mechanisms of mutant p53 overexpression and gain of function may help to develop novel strategies for cancer treatment. Wild type p53 stability is regulated by MDM2. which is an ubiquitin E3 ligase that binds and promotes ubiquitination of p53. It has been proposed that one mechanism of mutant p53 stabilization is loss of MDM2 induction by mutant p53. However, significant MDM2 expression occurs in certain cell lines and tumor samples with mutant p53, suggesting that additional mechanisms are also involved in p53 stabilization. We recently found that mutant p53 has a novel property of inducing MDM2 stabilization. We show that a panel of tumor cell lines with mutant p53 expresses stabilized MDM2. Transfection of mutant p53 also caused stabilization of MDM2 in p53-null cells. Stabilization of MDM2 requires complex formation with mutant p53 and possibly recruitment of hsp90 by mutant p53. MDM2 forms a complex with hsp90 through binding to mutant p53. Hsp90 inhibitors can accelerate MDM2 degradation in mutant p53 cell lines. We propose a working model in which mutant p53 binds to MDM2 and hsp90, hsp90 then inhibits the function of MDM2, resulting in stabilization of p53 and MDM2. We propose the following experiments to further investigate the mechanism and function of p53 and MDM2 stabilization. (1) Determine the role of hsp90 in MDM2 and p53 stabilization. (2) Investigate the mechanism of MDM2 inactivation by mutant p53 and hsp9u. (3) Investigate the role of MDM2 in mutant p53 gain of function. (4) Target MDM2 and hsp90 in tumor cells with mutant p53. These experiments should lead to a better understanding of the mechanism that controls mutant p53 and MDM2 levels in tumors and the mechanism of mutant p53 gain of function.