Peuget Sylvain, Selivanova Galina
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Cancers (Basel). 2021 Sep 28;13(19):4850. doi: 10.3390/cancers13194850.
p53 is a major tumor suppressor that integrates diverse types of signaling in mammalian cells. In response to a broad range of intra- or extra-cellular stimuli, p53 controls the expression of multiple target genes and elicits a vast repertoire of biological responses. The exact code by which p53 integrates the various stresses and translates them into an appropriate transcriptional response is still obscure. p53 is tightly regulated at multiple levels, leading to a wide diversity in p53 complexes on its target promoters and providing adaptability to its transcriptional program. As p53-targeted therapies are making their way into clinics, we need to understand how to direct p53 towards the desired outcome (i.e., cell death, senescence or other) selectively in cancer cells without affecting normal tissues or the immune system. While the core p53 transcriptional program has been proposed, the mechanisms conferring a cell type- and stimuli-dependent transcriptional outcome by p53 require further investigations. The mechanism by which p53 localizes to repressed promoters and manages its co-repressor interactions is controversial and remains an important gap in our understanding of the p53 cistrome. We hope that our review of the recent literature will help to stimulate the appreciation and investigation of largely unexplored p53-mediated repression.
p53是一种主要的肿瘤抑制因子，可整合哺乳动物细胞中多种类型的信号传导。响应广泛的细胞内或细胞外刺激，p53控制多个靶基因的表达，并引发大量的生物学反应。p53整合各种应激并将其转化为适当转录反应的确切机制仍不清楚。p53在多个水平上受到严格调控，导致其靶启动子上的p53复合物具有广泛的多样性，并为其转录程序提供适应性。随着针对p53的疗法进入临床，我们需要了解如何在不影响正常组织或免疫系统的情况下，在癌细胞中选择性地引导p53实现预期结果（即细胞死亡、衰老或其他）。虽然已经提出了核心p53转录程序，但p53赋予细胞类型和刺激依赖性转录结果的机制仍需进一步研究。p53定位于抑制性启动子并管理其共抑制因子相互作用的机制存在争议，仍然是我们对p53顺反组理解中的一个重要空白。我们希望我们对近期文献的综述将有助于激发对大量未被探索的p53介导的抑制作用的认识和研究。
