Lees Andrea, Sessler Tamas, McDade Simon
Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast BT9 7AE, UK.
Cancers (Basel). 2021 Jun 29;13(13):3257. doi: 10.3390/cancers13133257.
The p53 tumour suppressor is best known for its canonical role as "guardian of the genome", activating cell cycle arrest and DNA repair in response to DNA damage which, if irreparable or sustained, triggers activation of cell death. However, despite an enormous amount of work identifying the breadth of the gene regulatory networks activated directly and indirectly in response to p53 activation, how p53 activation results in different cell fates in response to different stress signals in homeostasis and in response to p53 activating anti-cancer treatments remains relatively poorly understood. This is likely due to the complex interaction between cell death mechanisms in which p53 has been activated, their neighbouring stressed or unstressed cells and the local stromal and immune microenvironment in which they reside. In this review, we evaluate our understanding of the burgeoning number of cell death pathways affected by p53 activation and how these may paradoxically suppress cell death to ensure tissue integrity and organismal survival. We also discuss how these functions may be advantageous to tumours that maintain wild-type p53, the understanding of which may provide novel opportunity to enhance treatment efficacy.
p53肿瘤抑制因子最为人所知的是其作为“基因组守护者”的典型作用，即响应DNA损伤激活细胞周期停滞和DNA修复，若损伤无法修复或持续存在，则触发细胞死亡。然而，尽管已有大量工作确定了因p53激活而直接和间接激活的基因调控网络的广度，但对于在稳态下p53激活如何因不同应激信号导致不同细胞命运，以及在响应p53激活的抗癌治疗时如何导致不同细胞命运，人们仍了解得相对较少。这可能是由于p53已被激活的细胞死亡机制、其邻近的应激或非应激细胞以及它们所处的局部基质和免疫微环境之间存在复杂的相互作用。在本综述中，我们评估了我们对受p53激活影响的细胞死亡途径数量不断增加的理解，以及这些途径如何可能自相矛盾地抑制细胞死亡以确保组织完整性和机体存活。我们还讨论了这些功能对维持野生型p53的肿瘤可能有何益处，对这一点的理解可能为提高治疗效果提供新机会。
