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Buitrago-Molina LE, Marhenke S, Becker D, et al. p53-Independent Induction of p21 Fails to Control Regeneration and Hepatocarcinogenesis in a Murine Liver Injury Model. Cell Mol Gastroenterol Hepatol. 2021;11(5):1387-1404doi: 10.1016/j.jcmgh.2021.01.006.
Buitrago-Molina, L. E., Marhenke, S., Becker, D., Geffers, R., Itzel, T., Teufel, A., Jaeschke, H., Lechel, A., Unger, K., Markovic, J., Sharma, A. D., Marquardt, J. U., Saborowski, M., Saborowski, A., & Vogel, A. (2021). p53-Independent Induction of p21 Fails to Control Regeneration and Hepatocarcinogenesis in a Murine Liver Injury Model. Cellular and molecular gastroenterology and hepatology, 11(5), 1387-1404. https://doi.org/10.1016/j.jcmgh.2021.01.006
Buitrago-Molina, Laura Elisa, et al. "p53-Independent Induction of p21 Fails to Control Regeneration and Hepatocarcinogenesis in a Murine Liver Injury Model." Cellular and molecular gastroenterology and hepatology vol. 11,5 (2021): 1387-1404. doi: https://doi.org/10.1016/j.jcmgh.2021.01.006
Buitrago-Molina LE, Marhenke S, Becker D, Geffers R, Itzel T, Teufel A, Jaeschke H, Lechel A, Unger K, Markovic J, Sharma AD, Marquardt JU, Saborowski M, Saborowski A, Vogel A. p53-Independent Induction of p21 Fails to Control Regeneration and Hepatocarcinogenesis in a Murine Liver Injury Model. Cell Mol Gastroenterol Hepatol. 2021;11(5):1387-1404. doi: 10.1016/j.jcmgh.2021.01.006. Epub 2021 Jan 21. PMID: 33484913; PMCID: PMC8024980.
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Cell Mol Gastroenterol Hepatol. 2021;11(5):1387-1404. doi: 10.1016/j.jcmgh.2021.01.006. Epub 2021 Jan 21.

p53-Independent Induction of p21 Fails to Control Regeneration and Hepatocarcinogenesis in a Murine Liver Injury Model.

Cellular and molecular gastroenterology and hepatology

Laura Elisa Buitrago-Molina, Silke Marhenke, Diana Becker, Robert Geffers, Timo Itzel, Andreas Teufel, Hartmut Jaeschke, André Lechel, Kristian Unger, Jovana Markovic, Amar Deep Sharma, Jens U Marquardt, Michael Saborowski, Anna Saborowski, Arndt Vogel

Affiliations

  1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  2. First Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
  3. Department of Cell Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
  4. Division of Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
  5. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
  6. Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
  7. Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.
  8. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. Electronic address: [email protected].

PMID: 33484913 PMCID: PMC8024980 DOI: 10.1016/j.jcmgh.2021.01.006

Abstract

BACKGROUND & AIMS: A coordinated stress and regenerative response is important after hepatocyte damage. Here, we investigate the phenotypes that result from genetic abrogation of individual components of the checkpoint kinase 2/transformation-related protein 53 (p53)/cyclin-dependent kinase inhibitor 1A (p21) pathway in a murine model of metabolic liver injury.

METHODS: Nitisinone was reduced or withdrawn in Fah

RESULTS: In a model of metabolic liver injury, loss of p53, but not Chk2, impairs the oxidative stress response and aggravates liver damage, indicative of a direct p53-dependent protective effect on hepatocytes. Cell-cycle control during chronic liver injury critically depends on the presence of both p53 and its downstream effector p21. In p53-deficient hepatocytes, unchecked proliferation occurs despite a strong induction of p21, showing a complex interdependency between p21 and p53. The increased regenerative potential in the absence of p53 cannot fully compensate the surplus injury and is not sufficient to promote survival. Despite the distinct phenotypes associated with the loss of individual components of the DNA damage response, gene expression patterns are dominated by the severity of liver injury, but reflect distinct effects of p53 on proliferation and the anti-oxidative stress response.

CONCLUSIONS: Characteristic phenotypes result from the genetic abrogation of individual components of the DNA damage-response cascade in a liver injury model. The extent to which loss of gene function can be compensated, or affects injury and proliferation, is related to the level at which the cascade is interrupted. Accession numbers of repository for expression microarray data: GSE156983, GSE156263, GSE156852, and GSE156252.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: CHK2; DNA Damage; HCC; Oxidative Stress Response

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