Park Sei-Kyoung, Park Sangeun, Pentek Christine, Liebman Susan W
Department of Pharmacology, University of Nevada, Reno, NV 89557, USA.
iScience. 2020 Dec 29;24(1):102000. doi: 10.1016/j.isci.2020.102000. eCollection 2021 Jan 22.
Mutations in the p53 tumor suppressor are frequent causes of cancer. Because p53 aggregates appear in some tumor cells, it has been suggested that p53 could also cause cancer by forming self-replicating protein aggregates (prions). Here, using yeast, we show that transient p53 overexpression induced the formation of p53 prion aggregates that were transmitted for >100 generations, found in lysate pellets, stained with Thioflavin T, and transmitted by cytoplasmic transfer, or transfection with lysates of cells carrying the prion or with p53 amyloid peptide. As predicted for a prion, transient interruption of p53 expression caused permanent p53 prion loss. Importantly, p53 transcription factor activity was reduced by prion formation suggesting that prion aggregation could cause cancer. p53 has also been found in liquid-like nuclear droplets in animal cell culture. In yeast, we found that liquid-like p53 foci appear in response to stress and disappear with stress removal.
p53肿瘤抑制基因的突变是癌症的常见病因。由于在一些肿瘤细胞中出现了p53聚集体，有人提出p53也可能通过形成自我复制的蛋白质聚集体（朊病毒）引发癌症。在此，我们利用酵母表明，短暂的p53过表达诱导形成了p53朊病毒聚集体，这些聚集体可传递超过100代，存在于裂解物沉淀中，用硫黄素T染色，并通过细胞质转移、或用携带朊病毒的细胞裂解物或p53淀粉样肽转染进行传递。正如对朊病毒的预测，p53表达的短暂中断导致p53朊病毒永久性丧失。重要的是，朊病毒形成会降低p53转录因子活性，这表明朊病毒聚集可能引发癌症。在动物细胞培养中还发现p53存在于液状核小滴中。在酵母中，我们发现液状p53病灶在应激时出现，应激消除后消失。
