Mouse Homolog of the Human TP53 R337H Mutation Reveals Its Role in Tumorigenesis

Ji-Hoon Park, Jie Li, Matthew F. Starost, Chengyu Liu, Jie Zhuang, Jichun Chen, Maria I. Achatz, Ju-Gyeong Kang, Ping-yuan Wang, Sharon A. Savage, Paul M. Hwang
2018 Cancer Research  
Inheritance of germline mutations in the tumor suppressor gene TP53 causes Li-Fraumeni syndrome (LFS), a cancer predisposition disorder. The arginine to histidine substitution at amino acid position 337 of p53 (R337H) is a founder mutation highly prevalent in southern and southeastern Brazil and is considered an LFS mutation. Although this mutation is of significant clinical interest, its role in tumorigenesis using animal models has not been described. Here, we generate a knockin mouse model
more » ... ntaining the homologous R337H mutation (mouse R334H). De novo tumorigenesis was not significantly increased in either heterozygous (p53 334R/H ) or homozygous (p53 334H/H ) p53 R334H knockin mice compared with wild-type mice. However, susceptibility to diethylnitrosamine (DEN)-induced liver carcinogenesis was increased in a mutant allele dose-dependent manner. In parallel, p53 334H/H mice exposed to DEN exhibited increased DNA damage but decreased cell-cycle regulation in the liver. Oligomerization of p53, which is required for transactivation of target genes, was reduced in R334H liver, consistent with its decreased nuclear activity compared with wild-type. By modeling a TP53 mutation in mice that has relatively weak cancer penetrance, this study provides in vivo evidence that the human R337H mutation can compromise p53 activity and promote tumorigenesis. Significance: A germline mutation in the oligomerization domain of p53 decreases its transactivation potential and renders mice susceptible to carcinogen-induced liver tumorigenesis. Cancer Res; 78(18); 5375-83. Ó2018 AACR. Materials and Methods Generation of p53 R334H knockin mouse All animal studies were approved by the Institutional Animal Care and Use Committee of the NHBLI-NIH. The p53 R334H knockin mouse was made using the conventional embryonic stem (ES) cell-mediated strategy. Briefly, a gene-targeting construct containing the CGC (Arg) to CAC (His) missense mutation and
doi:10.1158/0008-5472.can-18-0016 pmid:30042151 fatcat:vp5k2jldkramtmxhhoe7wwuz6y