Oncogenic and teratogenic effects of p53Y217C, a mouse model of the human hotspot mutant p53Y220C

Abstract Missense “hotspot” mutations localized in six p53 codons account for 20% of TP53 mutations in human cancers. Hotspot p53 mutants have lost the tumor suppressive functions of the wildtype protein, but whether they may gain additional functions promoting tumorigenesis remains controversial. Here we generated Trp53Y217C, a mouse model of the human hotspot mutant TP53Y220C. DNA damage responses were lost in p53Y217C/Y217C cells. Surprisingly, intercrosses from p53+/Y217C heterozygotes yielded only one p53Y217C/Y217C female for nineteen p53Y217C/Y217C males at weaning, a skewed distribution explained by the high frequency of p53Y217C/Y217C female embryos with exencephaly and the death of most p53Y217C/Y217C female neonates. Furthermore, parturition was impaired in pregnant p53Y217C/Y217C females. Finally, p53Y217C/Y217C males died earlier than p53-/- males, with more aggressive thymic lymphomas. Together, these data indicate that the p53Y217C mutation not only abrogates wildtype p53 functions, but also exerts additional effects promoting oncogenesis in males and teratogenesis or dystocia in females.