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.

大多数癌症的进化都会导致 p53 通路失效，这是一种防止转化和恶性细胞生长的关键肿瘤抑制机制。然而，只有约 50% 的 p53 表现出失活突变，而其余的其活性则受到调节途径的蛋白质变化的抑制。因此，在仍为野生型的细胞中恢复 p53 活性是一种非常有吸引力的治疗策略，可以对许多不同的癌症类型有效。为此，可以使用药物通过调节其调节途径来稳定 p53 水平。然而，尽管出现了有希望的策略，但药物开发在临床试验中却陷入停滞。对替代方法的需求已将焦点转移到 14-3-3 蛋白质家族，该家族通过直接和间接相互作用强烈影响 p53 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，特别强调了它们与途径不同成员结合所涉及的机制。这些信息对于设计能够通过影响蛋白质-蛋白质相互作用来重新激活癌细胞中的 p53 的新化合物非常重要。14-3-3 异构体和 p53 通路之间的复杂关系表明，可以识别和利用 p53 重新激活的许多潜在药物靶点来设计具有广泛应用的新型抗肿瘤疗法。