4.8 Article

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

Journal

EMBO JOURNAL
Volume 38, Issue 20, Pages -

Publisher

WILEY
DOI: 10.15252/embj.2019102096

Keywords

apoptosis; Mdm2; mutant p53; p53; tumor suppression

Funding

  1. Deutsche Forschungsgemeinschaft (DFG) [DFG STI 182/7-1, TI 1028/2-1]
  2. Deutsche Krebshilfe [111250, 111444, 70112623]
  3. Deutsche Jose Carreras Leukamie Stiftung e.V. [DJCLS R 13/08, 09 R/2018]
  4. Bundesministerium fur Bildung und Forschung [BMBF 031L0063]
  5. German Center for Lung Research (DZL)

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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.

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