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: 10315918
• 负责人: Zhaohui Feng
• 金额: $ 41.31万
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10315918
• 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.

抽象的 肿瘤抑制p53是人类癌症中最常见的突变基因，包括结直肠癌 （CRC）。许多与肿瘤相关的突变体P53（MUTP53）蛋白不仅失去了肿瘤抑制功能 野生型p53，但也获得了新的致癌活性以促进肿瘤发生，这被定义为 “功能收益”（GOF）。 MUTP53蛋白通常会变得稳定，并积累到很高的水平 癌症，这对于肿瘤发生中的Mutp53 GOF至关重要。不稳定的MUTP53蛋白正在积极地 作为一种新颖的癌症治疗策略测试。但是，mutp53的机制 癌症积累的理解很少，这阻碍了有效策略的发展 癌症治疗。 MDM2是p53的最关键的负调节剂。 MDM2同工型B（MDM2B），剪接 MDM2的同工型在人类癌症中经常过表达，并且在 肿瘤发生。目前，MDM2B介导的MUTP53积累和 癌症中的MDM2B过表达知之甚少。识别其基本机制具有 开发有效策略来治疗携带MUTP53的癌症的直接潜力。这项研究的目的是 确定MUTP53在CRC中积累的机制，以提供新的热目标/策略 用于携带MUTP53的CRC。根据我们的初步研究，我们假设MDM2B过表达 是CRC中的MUTP53蛋白积累和GOF的关键机制，此外， MDM2B及其信号通路可以用于携带MUTP53的CRC治疗。我们将测试我们的 通过以下特定目的假设：1）确定MDM2B过表达是否是关键机制 使用不同的小鼠结直肠肿瘤模型在CRC中的基础MUTP53积累和GOF，以及 确定MDM2B介导的MUTP53积累的机制； 2）确定机制 CRC中的基础MDM2B过表达，并测试是否靶向MDM2B及其信号通路 可以抑制CRC中的MUTP53积累和GOF。我们预计这项拟议的研究将提供新的 有关MUTP53积累，MDM2B肿瘤促进功能和MDM2B的范例 CRC中的过表达。如果成功完成，这项研究的结果将有可能发展 MDM2B及其信号通路是携带MUTP53的CRC的新型热目标。