The African-specific S47 polymorphism of p53 alters chemosensitivity

Abstract

The TP53 protein is known to affect the sensitivity of tumor cells to cell death by DNA damaging agents. We recently reported that human and mouse cells containing an African-specific coding region variant of p53, Pro47Ser (hereafter S47), are impaired in the transactivation of a small subset of p53 target genes including GLS2 and SCO2, and are markedly resistant to cisplatin. Further, mice containing this variant are markedly predisposed to cancer. Together these findings suggested that cancer-affected humans with the S47 variant might not be effectively treated with cisplatin. To more directly test this premise, we created transformed derivatives of mouse embryo fibroblasts (MEFs) containing wild type p53 (WT) and the S47 variant and analyzed them for chemosensitivity. We find that transformation with E1A and Ras actually reverses the chemosensitivity/transcriptional differences between WT p53 and S47. Specifically, E1A/Ras-transformed S47 cells show increased sensitivity to cisplatin and paclitaxel, and comparable transactivation of GLS2 and SCO2, compared to cells with WT p53. These data suggest that the functional differences between WT p53 and S47 in primary cells may not hold true for transformed cells. They also offer hope that cisplatin and paclitaxel may be effective chemotherapeutic drugs for S47 individuals with cancer.

Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53

“…In this work, we have tried to maintain more relevant concentrations of glutathione, and under these conditions the differences in ferroptosis resistance in S47 cells are most dramatic. Additionally, we show compelling data that CCl 4 , which has been reported to induce iron accumulation, cell death by lipid peroxidation, and GSH depletion (37), is a bona fide inducer of ferroptosis in the liver. Moreover, we confirm the defect in ferroptosis in S47 livers that was seen in cultured cells.…”

“…A SNP affecting codon 47 of TP53 directs the insertion of either a proline (P47) or a serine (S47) in the protein (Pro47Ser, rs1800371, G/A). Interestingly, the presence of the S47 variant appears to be largely restricted to African-descent populations, at a minor allele frequency of ∼4% in Africans and 1% in African Americans (4,(6)(7)(8). Our prior studies showed that cells expressing the P47 and S47 isoforms generally exhibit a similar ability to induce apoptosis in response to most DNAdamaging agents and several chemotherapeutics.…”

“…Human TP53 harbors naturally occurring SNPs that impact function (4,5). A SNP affecting codon 47 of TP53 directs the insertion of either a proline (P47) or a serine (S47) in the protein (Pro47Ser, rs1800371, G/A).…”

P53‐dependent induction of ferroptosis is required for artemether to alleviate carbon tetrachloride‐induced liver fibrosis and hepatic stellate cell activation

“…Traditionally, we generally accepted that P53 presented antitumor effect by modulating cell‐cycle arrest, apoptosis, and senescence . However, more and more documents suggested that P53 was also critical for inducing ferroptosis . Li et al validated in p53‐mediated ferroptosis played a critical role in suppressing tumor formation in vivo and revealed that the combination of genomic instability and activation of ferroptosis may promote aging‐associated phenotypes .…”

The Religious Preconditions for the Race Concept in Modern Science

“…Recently, geneticists working at the Wistar Institute in Philadelphia claim to have found a single gene variant that may explain why Black Americans with common cancers are less likely to survive than other races (Basu et al. ). The Wistar Institute is the first independent nonprofit biomedical research organization in the country and has held the Cancer Center designation from the National Cancer Institute since the 1970s.…”