期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 17, 页码 8390-8396出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1821277116
关键词
p53; coenzyme A; ferroptosis; S-thiolation; polymorphism
资金
- National Institutes of Health [NIH R01 CA139319, R01 CA102184, P01 CA114046]
- NIH [NIH P30 DK050306, P01 CA098101, P01 DK049210]
- Cancer Center Support Grant [CA010815]
A population-restricted single-nucleotide coding region polymorphism (SNP) at codon 47 exists in the human TP53 gene (P47S, hereafter P47 and S47). In studies aimed at identifying functional differences between these variants, we found that the African-specific S47 variant associates with an impaired response to agents that induce the oxidative stress-dependent, nonapoptotic cell death process of ferroptosis. This phenotype is manifested as a greater resistance to glutamate-induced cytotoxicity in cultured cells as well as increased carbon tetrachloride-mediated liver damage in a mouse model. The differential ferroptotic responses associate with intracellular antioxidant differences between P47 and 547 cells, including elevated abundance of the low molecular weight thiols coenzyme A (CoA) and glutathione in 547 cells. Importantly, the disparate ferroptosis phenotypes related to the P475 polymorphism are reversible. Exogenous administration of CoA provides protection against ferroptosis in cultured mouse and human cells, as well as in a mouse model. The combined data support a positive role for p53 in ferroptosis and identify CoA as a regulator of this cell death process. Together, these findings provide mechanistic insight linking redox regulation of p53 to small molecule antioxidants and stress signaling pathways. They also identify potential therapeutic approaches to redox-related pathologies.
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