Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer.
Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer.
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14-3-3蛋白相互作用网络对p53的调控：癌症药物发现的新机遇。
DOI：
10.1038/s41420-020-00362-3
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发表时间：
2020-11-16
影响因子：
7
通讯作者：
Doveston RG
中科院分区：
文献类型：
--
作者：
Falcicchio M;Ward JA;Macip S;Doveston RG
大多数癌症的进化会使p53通路失效，而p53通路是一种关键的肿瘤抑制机制，可以阻止转化和恶性细胞的生长。然而，只有约50%的人表现出p53失活突变，而在其余情况下，其活性受到调节该途径的蛋白质变化的抑制。因此，在细胞中恢复p53活性是一种非常有吸引力的治疗策略，可能对许多不同类型的癌症有效。为此，可以使用药物通过调节p53的调控途径来稳定其水平。然而，尽管出现了有希望的策略，药物开发却在临床试验中停滞不前。对替代方法的需求已将焦点转移到14-3-3蛋白家族，该蛋白家族通过直接和间接的相互作用强烈影响p53的稳定性和转录活性。在这里，我们首次详细回顾了14-3-3蛋白如何调节p53，特别强调了它们与该途径不同成员结合的机制。这一信息对于设计能够通过影响蛋白-蛋白相互作用来重新激活癌细胞中p53的新化合物非常重要。14-3-3亚型与p53通路之间的复杂关系表明，许多p53再激活的潜在药物靶点可以被识别和利用，以设计具有广泛应用的新型抗肿瘤疗法。
Most cancers evolve to disable the p53 pathway, a key tumour suppressor mechanism that prevents transformation and malignant cell growth. However, only ~50% exhibit inactivating mutations of p53, while in the rest its activity is suppressed by changes in the proteins that modulate the pathway. Therefore, restoring p53 activity in cells in which it is still wild type is a highly attractive therapeutic strategy that could be effective in many different cancer types. To this end, drugs can be used to stabilise p53 levels by modulating its regulatory pathways. However, despite the emergence of promising strategies, drug development has stalled in clinical trials. The need for alternative approaches has shifted the spotlight to the 14-3-3 family of proteins, which strongly influence p53 stability and transcriptional activity through direct and indirect interactions. Here, we present the first detailed review of how 14-3-3 proteins regulate p53, with special emphasis on the mechanisms involved in their binding to different members of the pathway. This information will be important to design new compounds that can reactivate p53 in cancer cells by influencing protein–protein interactions. The intricate relationship between the 14-3-3 isoforms and the p53 pathway suggests that many potential drug targets for p53 reactivation could be identified and exploited to design novel antineoplastic therapies with a wide range of applications.
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