An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model

Abstract

In this study, Jennis et al. characterize the first mouse model of an African-specific naturally occurring coding region variant at codon 47 of the p53 tumor suppressor gene (S47). They show that homozygous S47 mice are markedly tumor-prone and that the S47 variant impairs not only p53-mediated cell death but also the ability of p53 to transactivate a subset of genes involved in metabolism and ferroptosis.

Abstract

A nonsynonymous single-nucleotide polymorphism at codon 47 in TP53 exists in African-descent populations (P47S, rs1800371; referred to here as S47). Here we report that, in human cell lines and a mouse model, the S47 variant exhibits a modest decrease in apoptosis in response to most genotoxic stresses compared with wild-type p53 but exhibits a significant defect in cell death induced by cisplatin. We show that, compared with wild-type p53, S47 has nearly indistinguishable transcriptional function but shows impaired ability to transactivate a subset of p53 target genes, including two involved in metabolism: Gls2 (glutaminase 2) and Sco2. We also show that human and mouse cells expressing the S47 variant are markedly resistant to cell death by agents that induce ferroptosis (iron-mediated nonapoptotic cell death). We show that mice expressing S47 in homozygous or heterozygous form are susceptible to spontaneous cancers of diverse histological types. Our data suggest that the S47 variant may contribute to increased cancer risk in individuals of African descent, and our findings highlight the need to assess the contribution of this variant to cancer risk in these populations. These data also confirm the potential relevance of metabolism and ferroptosis to tumor suppression by p53.