2. Academic Validation
  3. Mouse models to investigate in situ cell fate decisions induced by p53

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

  • EMBO J. 2024 Oct;43(19):4406-4436. doi: 10.1038/s44318-024-00189-z.
Elizabeth Lieschke 1 2 3,  Annabella F Thomas 1 2,  Andrew Kueh 1 2 4 5,  Georgia K Atkin-Smith 1 2,  Pedro L Baldoni 1 2,  John E La Marca 1 2 4 5,  Savannah Young 1,  Allan Shuai Huang 1 2,  Aisling M Ross 1 6,  Lauren Whelan 1,  Deeksha Kaloni 1 2,  Lin Tai 1 4,  Gordon K Smyth 1 7,  Marco J Herold 1 2 4 5,  Edwin D Hawkins 1 2,  Andreas Strasser # 8 9,  Gemma L Kelly # 10 11
Affiliations

Affiliations

  • 1 The Walter and Eliza Hall Institute (WEHI), Melbourne, VIC, Australia.
  • 2 Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia.
  • 3 Oncogene Biology Laboratory, Francis Crick Institute, London, United Kingdom.
  • 4 Olivia Newton-John Cancer Research Institute, Melbourne, VIC, Australia.
  • 5 School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia.
  • 6 School of Medicine, Bernal Institute, Limerick Digital Cancer Research Centre & Health Research Institute, University of Limerick, Limerick, Ireland.
  • 7 School of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, Australia.
  • 8 The Walter and Eliza Hall Institute (WEHI), Melbourne, VIC, Australia. strasser@wehi.edu.au.
  • 9 Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia. strasser@wehi.edu.au.
  • 10 The Walter and Eliza Hall Institute (WEHI), Melbourne, VIC, Australia. gkelly@wehi.edu.au.
  • 11 Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia. gkelly@wehi.edu.au.
  • # Contributed equally.
PMID: 39160273 DOI: 10.1038/s44318-024-00189-z
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.

Keywords

Apoptosis; Cancer; Cell Cycle Arrest; Reporter Mice; p53/TRP53/TP53.

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