Systems Biology of the Stress Response, Department of Biology, Technical University of Darmstadt, Germany.
FEBS J. 2022 Jan;289(1):40-52. doi: 10.1111/febs.15767. Epub 2021 Mar 1.
p53 plays a central role in defending the genomic integrity of our cells. In response to genotoxic stress, this tumour suppressor orchestrates the expression of hundreds of target genes, which induce a variety of cellular outcomes ranging from damage repair to induction of apoptosis. In this review, we examine how the p53 response is regulated on several levels in individual cells to allow precise and context-specific fate decisions. We discuss that the p53 response is not only controlled by its canonical regulators but also controlled by interconnected signalling pathways that influence the dynamics of p53 accumulation upon damage and modulate its transcriptional activity at target gene promoters. Additionally, we consider how the p53 response is diversified through a variety of mechanisms at the promoter level and beyond to induce context-specific outcomes in individual cells. These layers of regulation allow p53 to react in a stimulus-specific manner and fine-tune its signalling according to the individual needs of a given cell, enabling it to take the right decision on survival or death.
p53 在保护细胞基因组完整性方面发挥着核心作用。在应对遗传毒性应激时，这种肿瘤抑制因子协调数百个靶基因的表达，诱导从损伤修复到细胞凋亡诱导等多种细胞结果。在这篇综述中，我们研究了 p53 反应如何在单个细胞的多个水平上受到调节，以允许精确和特定于上下文的命运决定。我们讨论了 p53 反应不仅受到其经典调节剂的控制，还受到相互关联的信号通路的控制，这些信号通路影响损伤时 p53 积累的动力学，并调节其在靶基因启动子上的转录活性。此外，我们还考虑了 p53 反应如何通过启动子水平及其他层面的多种机制多样化，以在单个细胞中诱导特定于上下文的结果。这些调节层允许 p53 以刺激特异性的方式反应，并根据给定细胞的个体需求微调其信号，使其能够在生存或死亡方面做出正确的决策。
