The regulation of mutant p53 protein accumulation in cancer: molecular basis and therapeutic potential

癌症中突变 p53 蛋白积累的调节：分子基础和治疗潜力

• 批准号: 10406369
• 负责人: Zhaohui Feng
• 金额: $ 41万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406369
• 关键词: BAG2 gene; Cessation of life; Clinic; Clinical; Colon; Colorectal Cancer; Colorectal Neoplasms; Complex; Cytoplasm; Development; Feedback; Frequencies; Genes; Genetic Translation; Goals; Human; MDM2 gene; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Mutate; Mutation; Oncogenic; Pathway interactions; Phosphorylation; Play; Prognosis; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-akt; RNA Splicing; Regulation; Role; Signal Pathway; Signal Transduction; Specimen; Spliceosomes; TP53 gene; Testing; Therapeutic; Transgenic Mice; Ubiquitination; United States; base; cancer cell; cancer diagnosis; cancer therapy; colon cancer patients; colon tumorigenesis; colorectal cancer treatment; gain of function; improved; mouse model; mutant; new therapeutic target; novel; overexpression; targeted treatment; therapeutically effective; treatment response; tumor; tumorigenesis

Abstract Tumor suppressor p53 is the most frequently mutated gene in human cancer, including colorectal cancer (CRC). Many tumor-associated mutant p53 (mutp53) proteins not only lose the tumor suppressive function of wild-type p53, but also gain new oncogenic activities to promote tumorigenesis, which is defined as the “gain-of-function” (GOF). Mutp53 proteins often become stable and accumulate to very high levels in cancer, which is critical for mutp53 GOF in tumorigenesis. Destabilizing mutp53 protein is being actively tested as a novel and promising strategy for cancer therapy. However, the mechanism of mutp53 accumulation in cancer is poorly understood, which hinders the development of effective strategies for cancer therapy. MDM2 is the most critical negative regulator of p53. MDM2 isoform B (MDM2B), a spliced isoform of MDM2, is frequently overexpressed in human cancer, and plays an important role in tumorigenesis. Currently, the mechanisms underlying MDM2B-mediated mutp53 accumulation and MDM2B overexpression in cancer are poorly understood. Identifying their underlying mechanisms has the direct potential to develop effective strategies to treat cancers carrying mutp53. The goal of this study is to determine the mechanism of mutp53 accumulation in CRC to provide novel therapeutic targets/strategies for CRC carrying mutp53. Based on our preliminary studies, we hypothesize that MDM2B overexpression is a critical mechanism underlying mutp53 protein accumulation and GOF in CRC, and furthermore, MDM2B and its signaling pathway can be targeted for therapy in CRC carrying mutp53. We will test our hypothesis by following specific aims: 1) determine whether MDM2B overexpression is a critical mechanism underlying mutp53 accumulation and GOF in CRC using different mouse colorectal tumor models, and identify mechanisms underlying MDM2B-mediated mutp53 accumulation; and 2) identify mechanisms underlying MDM2B overexpression in CRC, and test whether targeting MDM2B and its signaling pathway can inhibit mutp53 accumulation and GOF in CRC. We anticipate that this proposed study will provide new paradigms regarding mutp53 accumulation, tumor-promoting function of MDM2B, and MDM2B overexpression in CRC. If accomplished successfully, results from this study will have potential to develop MDM2B and its signaling pathway as novel therapeutic targets for CRC carrying mutp53.

摘要 肿瘤抑制基因p53是人类肿瘤中最常见的突变基因，包括结直肠癌 （CRC）。许多肿瘤相关突变型p53（mutp 53）蛋白不仅丧失了肿瘤抑制功能， 野生型p53，但也获得新的致癌活性，以促进肿瘤发生，这被定义为 “功能增益”（GOF）。Mutp 53蛋白通常变得稳定，并积累到非常高的水平， 癌症，这是关键的mutp 53 GOF在肿瘤发生。去稳定mutp 53蛋白正在被积极地 作为一种新的有前途的癌症治疗策略进行了测试。然而，mutp 53的作用机制 对癌症中的积累知之甚少，这阻碍了有效策略的发展， 癌症治疗MDM 2是p53最关键的负调节因子。MDM 2亚型B（MDM 2 B），一种剪接的 MDM 2的同种型，经常在人类癌症中过表达，并且在癌症中起重要作用。 肿瘤发生目前，MDM 2B介导的mutp 53积累和 MDM 2B在癌症中的过度表达知之甚少。识别其潜在机制， 直接潜力开发有效的策略来治疗携带mutp 53的癌症。本研究的目的是 确定mutp 53在CRC中积累的机制，以提供新的治疗靶点/策略 对于携带mutp 53的CRC。基于我们的初步研究，我们假设MDM 2B过表达 是CRC中mutp 53蛋白积聚和GOF的关键机制，此外， MDM 2B及其信号通路可以在携带mutp 53的CRC中被靶向治疗。我们将测试我们的 通过以下特定目的来确定MDM 2B过表达是否是一种关键机制 使用不同的小鼠结肠直肠肿瘤模型在CRC中潜在的mutp 53积累和GOF，和 鉴定MDM 2B介导mutp 53积累的潜在机制;和2）鉴定机制 CRC中潜在的MDM 2B过表达，并测试是否靶向MDM 2B及其信号通路 可以抑制CRC中mutp 53的积聚和GOF。我们预计，这项研究将提供新的 关于mutp 53积累、MDM 2B的肿瘤促进功能和MDM 2B的范例 在CRC中过度表达。如果成功完成，这项研究的结果将有潜力发展 MDM 2B及其信号通路作为携带mutp 53的CRC的新治疗靶点。