The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
The Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia.
Cell Death Differ. 2022 May;29(5):961-971. doi: 10.1038/s41418-022-00996-z. Epub 2022 Apr 8.
The tumour suppressor TP53 is a master regulator of several cellular processes that collectively suppress tumorigenesis. The TP53 gene is mutated in ~50% of human cancers and these defects usually confer poor responses to therapy. The TP53 protein functions as a homo-tetrameric transcription factor, directly regulating the expression of ~500 target genes, some of them involved in cell death, cell cycling, cell senescence, DNA repair and metabolism. Originally, it was thought that the induction of apoptotic cell death was the principal mechanism by which TP53 prevents the development of tumours. However, gene targeted mice lacking the critical effectors of TP53-induced apoptosis (PUMA and NOXA) do not spontaneously develop tumours. Indeed, even mice lacking the critical mediators for TP53-induced apoptosis, G1/S cell cycle arrest and cell senescence, namely PUMA, NOXA and p21, do not spontaneously develop tumours. This suggests that TP53 must activate additional cellular responses to mediate tumour suppression. In this review, we will discuss the processes by which TP53 regulates cell death, cell cycling/cell senescence, DNA damage repair and metabolic adaptation, and place this in context of current understanding of TP53-mediated tumour suppression.
抑癌基因 TP53 是多种细胞过程的主控调节器，这些过程共同抑制肿瘤发生。TP53 基因在约 50%的人类癌症中发生突变，这些缺陷通常导致对治疗的反应不佳。TP53 蛋白作为同源四聚体转录因子发挥作用，直接调节约 500 个靶基因的表达，其中一些基因参与细胞死亡、细胞周期、细胞衰老、DNA 修复和代谢。最初，人们认为诱导细胞凋亡是 TP53 防止肿瘤发生的主要机制。然而，基因靶向敲除 TP53 诱导凋亡的关键效应物（PUMA 和 NOXA）的小鼠不会自发形成肿瘤。事实上，即使是缺乏 TP53 诱导凋亡、G1/S 细胞周期阻滞和细胞衰老的关键介质（PUMA、NOXA 和 p21）的小鼠也不会自发形成肿瘤。这表明 TP53 必须激活其他细胞反应来介导肿瘤抑制。在这篇综述中，我们将讨论 TP53 调节细胞死亡、细胞周期/细胞衰老、DNA 损伤修复和代谢适应的过程，并将其置于当前对 TP53 介导的肿瘤抑制的理解的背景下。
