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

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.

p53 defies convention again: a p53 mutant that has lost tumor suppression but still can kill

“…Since then, many laboratories had used the ability to complement Mdm2 loss in mouse development as a means to probe various functions of p53. In contrast to the classic experiments with p53 nullizygosity, the 178E allele failed to rescue Mdm2 loss, but rather showed embryonic lethality associated with apoptosis (Timofeev et al, 2019). As this allele lacks transcriptional function, this hinted that the non-nuclear activity of p53 may be retained in this mutant.…”

“…An engineered mutation in human p53, R181E, was shown to lose cooperativity. Timofeev et al extend and validate those findings by generating an in vivo mouse model with the equivalent murine mutation, R178E (Timofeev et al, 2019). In so doing, they confirm that the 178E mutation is transcriptionally inactive, and, as expected, has lost tumor-suppressing activity either for spontaneous tumorigenesis or in the context of two oncogenic activating mutations, Elmyc for B-cell lymphoma, or AML-ETO9a and oncogenic N-Ras for acute myeloid leukemia.…”

“…There is no evidence for any gainof-function activity for 178E as the tumor biology that is observed is indistinguishable from p53 null mice. Further, in contrast to these transcriptionally dead mutants, 178E appears to retain the ability to induce apoptosis, albeit under conditions in which Mdm2 expression is ablated or p53 expression is induced by ectopic chemotherapy (Fig 1E) (Timofeev et al, 2019).…”

“…Multiple laboratories have been exploring the possibility of targeting mutant p53, mainly by its destabilization, in combination with chemotherapy (Sabapathy & Lane, 2018). Timofeev et al (2019) expand this paradigm by identifying a novel engineered p53 mutation (E) that is transcriptionally dead, loses tumor suppression, but remarkably can mediate an apoptotic response that is not dependent on effects on gene expression. Given the diversity of ways in which loss of tumor suppression can be achieved (Fig 1), understanding the molecular mechanisms underlying specific mutants clearly is of paramount importance.…”

“…Indeed, Timofeev et al (2019) demonstrate that 178E p53 can localize to mitochondria and interact with Bcl-2 family members. Further validation is needed, but it is likely that Timofeev et al (2019) may have finally identified the elusive mutation in p53 that distinguishes its cytosolic from its nuclear activities. If this indeed proves to be the case, the observation that 178E is no longer tumor-suppressing would support the idea that the transcriptional function of p53 is essential for its ability to fully block oncogenesis.…”