1. Academic Validation
  2. Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses

Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses

  • EMBO J. 2019 Oct 15;38(20):e102096. doi: 10.15252/embj.2019102096.
Oleg Timofeev 1 Boris Klimovich 1 Jean Schneikert 1 Michael Wanzel 1 2 Evangelos Pavlakis 1 Julia Noll 1 Samet Mutlu 1 Sabrina Elmshäuser 1 Andrea Nist 3 Marco Mernberger 1 Boris Lamp 3 Ulrich Wenig 4 Alexander Brobeil 4 Stefan Gattenlöhner 4 Kernt Köhler 5 Thorsten Stiewe 1 2 3
Affiliations

Affiliations

  • 1 Institute of Molecular Oncology, Philipps-University, Marburg, Germany.
  • 2 German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center, Marburg, Germany.
  • 3 Genomics Core Facility, Philipps University, Marburg, Germany.
  • 4 Institute of Pathology, Justus Liebig University, Giessen, Germany.
  • 5 Institute of Veterinary Pathology, Justus Liebig University, Giessen, Germany.
Abstract

Engineered p53 mutant mice are valuable tools for delineating p53 functions in tumor suppression and Cancer therapy. Here, we have introduced the R178E mutation into the Trp53 gene of mice to specifically ablate the cooperative nature of p53 DNA binding. Trp53R178E mice show no detectable target gene regulation and, at first sight, are largely indistinguishable from Trp53-/- mice. Surprisingly, stabilization of p53R178E in Mdm2-/- mice nevertheless triggers extensive Apoptosis, indicative of residual wild-type activities. Although this apoptotic activity suffices to trigger lethality of Trp53R178E ;Mdm2-/- embryos, it proves insufficient for suppression of spontaneous and oncogene-driven tumorigenesis. Trp53R178E mice develop tumors indistinguishably from Trp53-/- mice and tumors retain and even stabilize the p53R178E protein, further attesting to the lack of significant tumor suppressor activity. However, Trp53R178E tumors exhibit remarkably better chemotherapy responses than Trp53-/- ones, resulting in enhanced eradication of p53-mutated tumor cells. Together, this provides genetic proof-of-principle evidence that a p53 mutant can be highly tumorigenic and yet retain apoptotic activity which provides a survival benefit in the context of Cancer therapy.

Keywords

Mdm2; apoptosis; mutant p53; p53; tumor suppression.

Figures
Products