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

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. Synopsis In addition to its role as a transcription factor, p53 has non‐transcriptional activities. A DNA binding cooperativity mutant p53 mouse genetically separates these functions and reveals a prominent role for non‐transcriptional apoptotic p53 activities in development and cancer therapy responses. p53 cooperativity mutant Trp53 R178E is deficient for DNA binding and target gene activation. Trp53 R178E ‐mutant mice develop tumors as fast and extensively as Trp53 ‐knockout mice. Constitutive stabilization of Trp53 R178E in Mdm2 ‐knockout mice triggers widespread apoptosis and embryonic lethality. Stabilized Trp53 R178E and human TP53 R181E induce non‐transcriptional apoptosis in response to DNA damage and sensitize tumors to chemotherapy. Graphical Abstract Genetic in vivo analyses reveal non‐transcriptional apoptotic p53 roles in development and cancer.