Stabilization of MDM2 by mutant p53

突变体 p53 对 MDM2 的稳定作用

• 批准号: 6909035
• 负责人: JIANDONG CHEN
• 金额: $ 24.11万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909035
• 关键词: athymic mouse; carcinogenesis; cell transformation; heat shock proteins; mutant; neoplasm /cancer genetics; neoplastic process; p53 gene /protein; phosphorylation; point mutation; protein binding; protein protein interaction; protein structure function; protooncogene; tissue /cell culture; transfection /expression vector; tumor suppressor genes; tumor suppressor proteins; ubiquitin; western blottings

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.

描述：(申请人提供)近50%的人类肿瘤含有 DNA结合核心域中的p53点突变，这通常会导致 P53的过度表达是由于稳定所致。某些p53构象突变 也可以通过获得功能来促进转型。阐明其作用机制 突变型P53的过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的稳定性受MDM2调控。 它是一种泛素E3连接酶，结合并促进P53的泛素化。 已有研究提出突变型P53基因稳定的一种机制是缺失 突变型p53诱导MDM2的研究。然而，MDM2的显著表达发生在 某些带有突变型p53的细胞系和肿瘤样本，表明 其他机制也参与了P53的稳定。我们最近发现 突变型p53具有诱导MDM2稳定的新特性。我们展示了 一组带有突变型p53的肿瘤细胞系表达稳定的MDM2。 突变型P53基因的转导也能稳定P53阴性细胞中的MDM2。 MDM2的稳定需要与突变型p53形成复合体，并可能 突变型P53对HSP90的募集作用MDM2与HSP90通过 与突变型P53结合。HSP90抑制剂可加速MDM2在脑内的降解 突变型P53细胞株。我们提出了一个工作模型，在该模型中突变的p53结合到 MDM2和HSP90、HSP90然后抑制MDM2的功能，导致 P53和MDM2的稳定。我们建议进行以下实验，以进一步 探讨P53和MDM2稳定作用的机制和功能。(1) 确定HSP90在MDM2和P53稳定中的作用。(2)调查 突变型p53和hsp9u灭活mdm2的机制。(3)调查 MDM2在突变型P53功能增强中的作用(4)肿瘤靶向MDM2和HSP90 带有突变型P53的细胞。这些实验应该会让我们更好地理解 肿瘤中控制突变型P53和MDM2水平的机制以及 突变型P53功能增强的机制。