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 and how they may gain additional functions promoting tumorigenesis remain controversial. Here, we generated
Trp53
Y217C
, a mouse model of the human hotspot mutant
TP53
Y220C
. DNA damage responses were lost in
Trp53
Y217C/Y217C
(
Trp53
YC/YC
) cells, and
Trp53
YC/YC
fibroblasts exhibited increased chromosome instability compared to
Trp53
-/-
cells. Furthermore,
Trp53
YC/YC
male mice died earlier than
Trp53
-/-
males, with more aggressive thymic lymphomas. This correlated with an increased expression of inflammation-related genes in
Trp53
YC/YC
thymic cells compared to
Trp53
-/-
cells. Surprisingly, we recovered only one
Trp53
YC/YC
female for 22
Trp53
YC/YC
males at weaning, a skewed distribution explained by a high frequency of
Trp53
YC/YC
female embryos with exencephaly and the death of most
Trp53
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
Trp53
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.
