Illuminating p53 function in cancer with genetically engineered mouse models.
Illuminating p53 function in cancer with genetically engineered mouse models.
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DOI：
10.1016/j.semcdb.2013.12.014
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发表时间：
2014-03
影响因子：
7.3
通讯作者：
Attardi, Laura D.
中科院分区：
文献类型：
--
作者：
Garcia, Patty B.;Attardi, Laura D.
p53蛋白在肿瘤抑制中的关键作用通过其在人类癌症中的频繁突变和p53缺失小鼠的完全渗透性癌症易感性而突出。除了为p53在肿瘤抑制中的关键功能提供明确的证据外，基因工程小鼠模型还为p53功能提供了许多额外的见解。表达肿瘤来源的p53突变体的p53敲入小鼠揭示了这些突变体显示出积极促进癌发生的功能获得活性。在p53的不同结构域中具有改变的p53敲入突变体的产生有助于进一步阐明p53的细胞和生物化学活性，这是肿瘤抑制的最基本的。此外，通过产生在p53翻译后修饰（PTM）位点具有突变的p53敲入小鼠品系来调节p53翻译后修饰（PTM）状态揭示了p53调节的微妙性和复杂性。对扰乱p53上游调节因子的小鼠模型的分析已经巩固了p53途径可以通过直接p53突变以外的方式受到损害的概念。最后，允许肿瘤中p53再激活的可转换p53模型有助于评估p53恢复疗法用于癌症治疗的潜力。总的来说，小鼠模型极大地增强了我们对生理p53功能的理解，并将在未来的研究中继续提供新的生物学和临床见解。
The key role of the p53 protein in tumor suppression is highlighted by its frequent mutation in human cancers and by the completely penetrant cancer predisposition of p53 null mice. Beyond providing definitive evidence for the critical function of p53 in tumor suppression, genetically engineered mouse models have offered numerous additional insights into p53 function. p53 knock-in mice expressing tumor-derived p53 mutants have revealed that these mutants display gain-of-function activities that actively promote carcinogenesis. The generation of p53 knock-in mutants with alterations in different domains of p53 has helped further elucidate the cellular and biochemical activities of p53 that are most fundamental for tumor suppression. In addition, modulation of p53 post-translational modification (PTM) status by generating p53 knock-in mouse strains with mutations in p53 PTM sites has revealed a subtlety and complexity to p53 regulation. Analyses of mouse models perturbing upstream regulators of p53 have solidified the notion that the p53 pathway can be compromised by means other than direct p53 mutation. Finally, switchable p53 models that allow p53 reactivation in tumors have helped evaluate the potential of p53 restoration therapy for cancer treatment. Collectively, mouse models have greatly enhanced our understanding of physiological p53 function and will continue to provide new biological and clinical insights in future investigations.
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