Targeting Post-Translational Regulation of p53 in Colorectal Cancer by Exploiting Vulnerabilities in the p53-MDM2 Axis.
Targeting Post-Translational Regulation of p53 in Colorectal Cancer by Exploiting Vulnerabilities in the p53-MDM2 Axis.
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DOI：
10.3390/cancers14010219
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发表时间：
2022-01-03
期刊：
影响因子：
5.2
通讯作者：
Xie G
中科院分区：
文献类型：
--
作者：
Lai CW;Xie C;Raufman JP;Xie G
P53是一种关键的肿瘤抑制基因，在包括结直肠癌在内的肿瘤组织中经常发生突变。为了设计针对P53的抗癌策略，了解P53信号通路中无数细胞特异性的调节机制，以及这些调节机制如何被P53突变体逃避是至关重要的。这篇综述着重于结直肠癌，并考虑了野生型P53蛋白作用的调控机制，强调了在过去十年中的发现。我们专注于小鼠双分钟2同源基因(MDM2)的作用，它通过靶向P53蛋白降解来调节P53蛋白水平；还讨论了其他不依赖MDM2的机制。这些调控机制将在p53错义突变的背景下进一步研究，这些突变可以逃避规范的调控。最后，我们考虑了在临床前试验或早期临床试验中针对携带p53突变的癌症进行靶向治疗的潜在策略。关键抑癌基因P53在肿瘤发生发展中的作用和P53突变对肿瘤发生发展的影响不断扩大。这篇综述主要集中在结直肠癌和过去十年中发现的对P53表达和活性的调节。这些新发现的调控机制包括：(1)直接调节小鼠双分钟2同源(MDM2)，一种E3泛素蛋白连接酶；(2)调节MDM2-P53的相互作用；(3)不依赖MDM2的P53的降解；(4)抑制P53核转位。我们将这些调控机制定位在P53错义突变的背景下，这些错义突变不仅避开了典型的P53降解机制，而且还表现出增强肿瘤生存和转移的功能获得表型。最后，我们讨论了针对携带p53突变的肿瘤的现有和潜在的治疗策略。
p53, a critical tumor suppressor, is commonly mutated in neoplasia, including colorectal cancer. To devise anti-cancer strategies targeting p53, it is crucial to understand the myriad cell-specific regulatory mechanisms in the p53 signaling pathway, and how these same regulatory mechanisms may be evaded by p53 mutants. This review focuses on colorectal cancer and considers the regulatory mechanisms underlying the actions of wild type p53 protein, emphasizing discoveries made in the last decade. We focus on the role of mouse double minute 2 homolog (MDM2), which modulates p53 protein levels by targeting p53 for protein degradation; other MDM2-independent mechanisms are also discussed. These regulatory mechanisms are further examined in the context of p53 missense mutants, which can evade canonical regulation. Lastly, we consider potential strategies for therapeutic targeting of p53 mutant-bearing cancers in preclinical testing or early-phase clinical trials. The role played by the key tumor suppressor gene p53 and the implications of p53 mutations for the development and progression of neoplasia continue to expand. This review focuses on colorectal cancer and the regulators of p53 expression and activity identified over the past decade. These newly recognized regulatory mechanisms include (1) direct regulation of mouse double minute 2 homolog (MDM2), an E3 ubiquitin-protein ligase; (2) modulation of the MDM2-p53 interaction; (3) MDM2-independent p53 degradation; and (4) inhibition of p53 nuclear translocation. We positioned these regulatory mechanisms in the context of p53 missense mutations, which not only evade canonical p53 degradation machinery but also exhibit gain-of-function phenotypes that enhance tumor survival and metastasis. Lastly, we discuss current and potential therapeutic strategies directed against p53 mutant-bearing tumors.
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影响因子：
11.5
作者：
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通讯作者：
Ganjei-Azar, Parvin
影响因子：
8
作者：
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作者：
Alexandrova, Evguenia M.;Mirza, Safia A.;Moll, Ute M.
通讯作者：
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影响因子：
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作者：
Alexandrova EM;Yallowitz AR;Li D;Xu S;Schulz R;Proia DA;Lozano G;Dobbelstein M;Moll UM
通讯作者：
Moll UM
影响因子：
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作者：
DITTMER, D;PATI, S;LEVINE, AJ
通讯作者：
LEVINE, AJ