@article{5bbc58c6085343a1bbe0aa88a4790c1c,
title = "p53-mediated redox control promotes liver regeneration and maintains liver function in response to CCl4",
abstract = "The p53 transcription factor coordinates wide-ranging responses to stress that contribute to its function as a tumour suppressor. The responses to p53 induction are complex and range from mediating the elimination of stressed or damaged cells to promoting survival and repair. These activities of p53 can modulate tumour development but may also play a role in pathological responses to stress such as tissue damage and repair. Using a p53 reporter mouse, we have previously detected strong induction of p53 activity in the liver of mice treated with the hepatotoxin carbon tetrachloride (CCl4). Here, we show that p53 functions to support repair and recovery from CCl4-mediated liver damage, control reactive oxygen species (ROS) and limit the development of hepatocellular carcinoma (HCC), in part through the activation of a detoxification cytochrome P450, CYP2A5 (CYP2A6 in humans). Our work demonstrates an important role for p53-mediated redox control in facilitating the hepatic regenerative response after damage and identifies CYP2A5/CYP2A6 as a mediator of this pathway with potential prognostic utility in human HCC.",
author = "Humpton, {Timothy J.} and Holly Hall and Christos Kiourtis and Colin Nixon and William Clark and Ann Hedley and Robin Shaw and Bird, {Thomas G.} and Karen Blyth and Vousden, {Karen H.}",
note = "Funding Information: We would like to thank the Core Facilities and Advanced Technologies at the CRUK Beatson Institute, in particular the animal facilities staff, the histology team, the Molecular Technologies group, and the Bioinformatics services. We thank Catherine Winchester for comments on the manuscript. TJH and KHV conceived and designed the project. HH analysed the RNA-seq data and liver TCGA-LIHC data. CK performed experiments with Mdm2Ex5/6Δ mice, for which funding was provided by TGB. CN performed IHC. WC performed RNA sequencing. AH and RS analysed RNA-seq data. TJH performed all other experiments and data analysis with assistance from HH. The work was supervised by TGB, KB and KHV. TJH and KHV wrote the manuscript and all authors discussed the results and revised and approved the manuscript prior to submission. This work was funded by Cancer Research UK grant C596/A26855 and supported by The Francis Crick Institute which receives its core funding from Cancer Research UK (FC001557), the United Kingdom Medical Research Council (FC001557), and the Wellcome Trust (FC001557), and the CRUK Beatson Institute which receives its core funding from Cancer Research UK grant C596/A17196. HH was funded by BBSRC grant BB/N017005/2. Additional funding for the work was provided by Cancer Research UK grant A29799 (KB). TGB was funded by the Wellcome Trust (Grant number: WT107492Z) and CRUK HUNTER Accelerator Award (Grant number: A26813). Funding Information: This work was funded by Cancer Research UK grant C596/A26855 and supported by The Francis Crick Institute which receives its core funding from Cancer Research UK (FC001557), the United Kingdom Medical Research Council (FC001557), and the Wellcome Trust (FC001557), and the CRUK Beatson Institute which receives its core funding from Cancer Research UK grant C596/A17196. HH was funded by BBSRC grant BB/N017005/2. Additional funding for the work was provided by Cancer Research UK grant A29799 (KB). TGB was funded by the Wellcome Trust (Grant number: WT107492Z) and CRUK HUNTER Accelerator Award (Grant number: A26813). Funding Information: KHV is on the board of directors and a shareholder of Bristol Myers Squibb, and on the science advisory board (with stock options) of PMV Pharma, RAZE Therapeutics and Volastra Therapeutics, Inc. She is also on the SAB of Ludwig Cancer Research. KHV is a co-founder and consultant of Faeth Therapeutics. She has been in receipt of research funding from Astex Pharmaceuticals and AstraZeneca and contributed to CRUK Cancer Research Technology filing of Patent Application WO/2017/144877. TGB is in receipt of research funding from AstraZeneca. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2022",
month = mar,
doi = "10.1038/s41418-021-00871-3",
language = "English",
volume = "29",
pages = "514--526",
journal = "Cell Death and Differentiation",
issn = "1350-9047",
publisher = "Springer Nature",
}