Journalartikel
Autorenliste: Timofeev, Oleg; Klimovich, Boris; Schneikert, Jean; Wanzel, Michael; Pavlakis, Evangelos; Noll, Julia; Mutlu, Samet; Elmshaeuser, Sabrina; Nist, Andrea; Mernberger, Marco; Lamp, Boris; Wenig, Ulrich; Brobeil, Alexander; Gattenloehner, Stefan; Koehler, Kernt; Stiewe, Thorsten
Jahr der Veröffentlichung: 2019
Zeitschrift: The EMBO Journal
Bandnummer: 38
Heftnummer: 20
ISSN: 0261-4189
eISSN: 1460-2075
Open Access Status: Hybrid
DOI Link: https://doi.org/10.15252/embj.2019102096
Verlag: EMBO Press
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. Trp53(R178E) mice show no detectable target gene regulation and, at first sight, are largely indistinguishable from Trp53(-/-) mice. Surprisingly, stabilization of p53(R178E) in Mdm2(-/-) mice nevertheless triggers extensive apoptosis, indicative of residual wild-type activities. Although this apoptotic activity suffices to trigger lethality of Trp53(R178E);Mdm2(-/-) embryos, it proves insufficient for suppression of spontaneous and oncogene-driven tumorigenesis. Trp53(R178E) mice develop tumors indistinguishably from Trp53(-/-) mice and tumors retain and even stabilize the p53(R178E) protein, further attesting to the lack of significant tumor suppressor activity. However, Trp53(R178E) 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.
Zitierstile
Harvard-Zitierstil: Timofeev, O., Klimovich, B., Schneikert, J., Wanzel, M., Pavlakis, E., Noll, J., et al. (2019) Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses, The EMBO Journal, 38(20), Article e102096. https://doi.org/10.15252/embj.2019102096
APA-Zitierstil: Timofeev, O., Klimovich, B., Schneikert, J., Wanzel, M., Pavlakis, E., Noll, J., Mutlu, S., Elmshaeuser, S., Nist, A., Mernberger, M., Lamp, B., Wenig, U., Brobeil, A., Gattenloehner, S., Koehler, K., & Stiewe, T. (2019). Residual apoptotic activity of a tumorigenic p53 mutant improves cancer therapy responses. The EMBO Journal. 38(20), Article e102096. https://doi.org/10.15252/embj.2019102096
Schlagwörter
CELL-CYCLE ARREST; DNA-BINDING COOPERATIVITY; MDM2; MDM2-DEFICIENT MICE; MOUSE MODELS; MUTANT P53; tumor suppression; TUMOR SUPPRESSION
