Oncogenic and teratogenic effects of <i>Trp53</i>^Y217C, an inflammation-prone mouse model of the human hotspot mutant <i>TP53</i>^Y220C.

Abstract

Missense 'hotspot' mutations localized in six p53 codons account for 20% of <i>TP53</i> mutations in human cancers. Hotspot p53 mutants have lost the tumor suppressive functions of the wildtype protein, but whether and how they may gain additional functions promoting tumorigenesis remain controversial. Here, we generated <i>Trp53</i>^Y217C, a mouse model of the human hotspot mutant <i>TP53</i>^Y220C. DNA damage responses were lost in <i>Trp53</i>^Y217C/Y217C (<i>Trp53</i>^YC/YC) cells, and <i>Trp53</i>^YC/YC fibroblasts exhibited increased chromosome instability compared to <i>Trp53</i>^-/- cells. Furthermore, <i>Trp53</i>^YC/YC male mice died earlier than <i>Trp53</i>^-/- males, with more aggressive thymic lymphomas. This correlated with an increased expression of inflammation-related genes in <i>Trp53</i>^YC/YC thymic cells compared to <i>Trp53</i>^-/- cells. Surprisingly, we recovered only one <i>Trp53</i>^YC/YC female for 22 <i>Trp53</i>^YC/YC males at weaning, a skewed distribution explained by a high frequency of <i>Trp53</i>^YC/YC female embryos with exencephaly and the death of most <i>Trp53</i>^YC/YC female neonates. Strikingly, however, when we treated pregnant females with the anti-inflammatory drug supformin (LCC-12), we observed a fivefold increase in the proportion of viable <i>Trp53</i>^YC/YC weaned females in their progeny. Together, these data suggest that the p53^Y217C mutation not only abrogates wildtype p53 functions but also promotes inflammation, with oncogenic effects in males and teratogenic effects in females.