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

摘要 抑癌基因P53是包括结直肠癌在内的人类癌症中最常见的突变基因 (CRC)。许多肿瘤相关突变型P53蛋白不仅失去抑瘤功能 野生型P53，但也获得新的致癌活性，以促进肿瘤的发生，这被定义为 “函数增益”(Gain-of-Function)。Mutp53蛋白通常变得稳定，并在体内积累到非常高的水平 癌症，这是突变P53基因在肿瘤发生中的关键作用。破坏稳定的突变型P53蛋白正在活跃 被测试为一种新的、有希望的癌症治疗策略。然而，突变P53的机制 人们对癌症中的积聚知之甚少，这阻碍了制定有效的治疗策略 癌症治疗。MDM2是P53最关键的负性调控因子。MDM2异构体B(MDM2B)，剪接 MDM2的异构体，在人类癌症中经常过度表达，并在 肿瘤发生学。目前，MDM2B介导的突变p53积聚和 MDM2B在癌症中的过度表达目前还知之甚少。识别它们的基本机制具有 开发治疗携带突变P53的癌症的有效策略的直接潜力。这项研究的目标是 确定大肠癌中突变P53积聚的机制以提供新的治疗靶点/策略 用于携带突变p53的结直肠癌。根据我们的初步研究，我们假设MDM2B过表达 是大肠癌中突变P53蛋白积聚和GOF的关键机制，而且， MDM2B及其信号通路可靶向治疗携带突变P53的大肠癌。我们将测试我们的 假设：1)确定MDM2B过度表达是否是一种关键机制 使用不同的小鼠结直肠肿瘤模型研究大肠癌中突变P53的积聚和GOF 识别MDM2B介导的突变p53积聚的机制；以及2)识别机制 MDM2B在结直肠癌中的过度表达，并检测是否针对MDM2B及其信号通路 能抑制大肠癌中突变的P53积聚和GOF。我们预计这项拟议的研究将提供新的 突变P53积聚、MDM2B和MDM2B促肿瘤功能的研究范式 结直肠癌中过度表达。如果成功完成，这项研究的结果将具有开发潜力 MDM2B及其信号通路作为携带突变P53的大肠癌新的治疗靶点。

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.