Stabilization of MDM2 by mutant p53

描述：（由申请人提供）近50%的人类肿瘤含有 DNA结合核心结构域中的p53点突变，这通常会导致 p53的过度表达是由于稳定。某些p53构象突变体 也可以通过功能的获得来促进转化。阐明机制 突变型p53的过度表达和功能的获得可能有助于开发新的 癌症治疗的策略。野生型p53稳定性受MDM2调节。 其是结合并促进p53泛素化的泛素E3连接酶。 已经提出突变型p53稳定化的一种机制是失活。 突变型p53对MDM2的诱导。然而，MDM2的显著表达发生在 某些细胞系和肿瘤样本与突变p53，这表明， 另外的机制也涉及p53的稳定。我们最近发现 突变型p53具有诱导MDM2稳定化的新特性。我们表明 一组具有突变型p53的肿瘤细胞系表达稳定的MDM2。 突变型p53的转染也引起p53缺失细胞中MDM2的稳定。 MDM2的稳定需要与突变型p53形成复合物，并且可能 突变型p53对hsp90的募集。MDM2与hsp90形成复合物， 与突变型p53结合。热休克蛋白90抑制剂可以加速MDM2降解， 突变型p53细胞系。我们提出了一个工作模型，其中突变型p53结合到 MDM2和hsp90，hsp90然后抑制MDM2的功能，导致 p53和MDM2的稳定化。我们提出以下实验，以进一步 探讨p53和MDM2的稳定机制和功能。（一） 确定热休克蛋白90在MDM2和p53稳定中的作用。(2)探讨 突变型p53和hsp9u对MDM2的失活机制。(3)探讨 MDM2在突变型p53功能获得中的作用。(4)靶向肿瘤中的MDM2和hsp90 突变型p53细胞这些实验应该能让我们更好地理解 控制肿瘤中突变型p53和MDM2水平的机制， 突变型p53功能获得的机制。

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.