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

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 (ironmediated 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.

Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis

“…Using Ingenuity pathway analysis, we found a hypothetical connection between PHKG2 and iron metabolism involving p53 (Fig. S3), which has itself been linked to ferroptosis regulation (48,49), providing an avenue for future exploration. Because we know that decreased iron levels suppress erastin lethality (6), this iron regulatory function of PHKG2 is likely responsible for modulating sensitivity to erastin.…”

Ironing out how p53 regulates ferroptosis

“…Transcriptionally, this variant showed impaired ability to repress SLC7A11 or transactivate GLS2. Indeed, both human and murine cells containing this variant were markedly defective at inducing ferroptosis, and silencing of GLS2 essentially phenocopied this defect in cells with wild-type p53 (19). At this point, the search was on for an elucidation of the pathway whereby p53 regulates ferroptosis.…”

Tumor suppression by p53 involves inhibiting an enabler, FGF13

“…Thus, it was unexpected when several different laboratories using in vivo mouse models demonstrated that these apoptotic and cell cycle effects of p53 were not needed for tumor suppression (10)(11)(12). More recently, it has been shown that another p53-mediated response, ferroptosis, may be a key player in tumor suppression (13,14). The current study by Bublik et al (1) adds another possible role for wild-type p53 in preventing cancer development, namely negatively regulating FGF13 expression and its effects on ribosomal RNA synthesis in the nucleolus.…”