Mouse models to investigate in situ cell fate decisions induced by p53.

IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Journal Pub Date : 2024-10-01 Epub Date: 2024-08-19 DOI:10.1038/s44318-024-00189-z
Elizabeth Lieschke, Annabella F Thomas, Andrew Kueh, Georgia K Atkin-Smith, Pedro L Baldoni, John E La Marca, Savannah Young, Allan Shuai Huang, Aisling M Ross, Lauren Whelan, Deeksha Kaloni, Lin Tai, Gordon K Smyth, Marco J Herold, Edwin D Hawkins, Andreas Strasser, Gemma L Kelly
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Abstract

Investigating how transcription factors control complex cellular processes requires tools that enable responses to be visualised at the single-cell level and their cell fate to be followed over time. For example, the tumour suppressor p53 (also called TP53 in humans and TRP53 in mice) can initiate diverse cellular responses by transcriptional activation of its target genes: Puma to induce apoptotic cell death and p21 to induce cell cycle arrest/cell senescence. However, it is not known how these processes are regulated and initiated in different cell types. Also, the context-dependent interaction partners and binding loci of p53 remain largely elusive. To be able to examine these questions, we here developed knock-in mice expressing triple-FLAG-tagged p53 to facilitate p53 pull-down and two p53 response reporter mice, knocking tdTomato and GFP into the Puma/Bbc3 and p21 gene loci, respectively. By crossing these reporter mice into a p53-deficient background, we show that the new reporters reliably inform on p53-dependent and p53-independent initiation of both apoptotic or cell cycle arrest/senescence programs, respectively, in vitro and in vivo.

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研究 p53 诱导的原位细胞命运决定的小鼠模型。
研究转录因子如何控制复杂的细胞过程需要一些工具,这些工具可以在单细胞水平上对反应进行可视化,并随时间推移跟踪其细胞命运。例如,肿瘤抑制因子 p53(在人类中也称为 TP53,在小鼠中则称为 TRP53)可以通过转录激活其靶基因来启动多种细胞反应:Puma诱导细胞凋亡,p21诱导细胞周期停滞/细胞衰老。然而,这些过程在不同类型的细胞中是如何调节和启动的尚不清楚。此外,p53 的相互作用伙伴和结合位点在很大程度上仍然难以捉摸。为了研究这些问题,我们在此开发了表达三重-FLAG 标记 p53 的基因敲入小鼠,以促进 p53 的下拉,并开发了两种 p53 反应报告小鼠,分别在 Puma/Bbc3 和 p21 基因位点敲入 tdTomato 和 GFP。通过将这些报告小鼠与 p53 缺陷背景杂交,我们发现新的报告小鼠能可靠地在体外和体内分别报告依赖 p53 和不依赖 p53 的细胞凋亡或细胞周期停滞/衰老程序的启动情况。
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来源期刊
EMBO Journal
EMBO Journal 生物-生化与分子生物学
CiteScore
18.90
自引率
0.90%
发文量
246
审稿时长
1.5 months
期刊介绍: The EMBO Journal has stood as EMBO's flagship publication since its inception in 1982. Renowned for its international reputation in quality and originality, the journal spans all facets of molecular biology. It serves as a platform for papers elucidating original research of broad general interest in molecular and cell biology, with a distinct focus on molecular mechanisms and physiological relevance. With a commitment to promoting articles reporting novel findings of broad biological significance, The EMBO Journal stands as a key contributor to advancing the field of molecular biology.
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