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The p53 tumor suppressor protein is a transcription factor and master stress response mediator, and it is subject to reduction-oxidation (redox)-dependent regulation. The P47S variant of TP53, which exists primarily in African-descent populations, associates with an elevated abundance of low molecular weight (LMW) thiols, including glutathione (GSH) and coenzyme A (CoA). Here we show that S47 and P47 cells exhibit distinct metabolic profiles, controlled by their different redox states and expression of Activating Transcription Factor-4 (ATF4). We find that S47 cells exhibit decreased catabolic glycolysis but increased use of the pentose phosphate pathway (PPP), and an enhanced abundance of the antioxidant, NADPH. We identify ATF4 as differentially expressed in P47 and S47 cells and show that ATF4 can reverse the redox status and rescue metabolism of S47 cells, as well as increase sensitivity to ferroptosis. This adaptive metabolic switch is rapid, reversible, and accompanied by thiol-mediated changes in the structures and activities of key glycolytic signaling pathway proteins, including GAPDH and G6PD. The results presented here unveil the important functional interplay among pathways regulating thiol-redox status, metabolic adaptation, and cellular responses to oxidative stress. [ABSTRACT FROM AUTHOR]

The TP53 gene is well known to be the most frequently mutated gene in human cancer. In addition to mutations, there are > 20 different coding region single-nucleotide polymorphisms (SNPs) in the TP53 gene, as well as SNPs in MDM2, the negative regulator of p53. Several of these SNPs are known to alter p53 pathway function. This makes p53 rather unique among cancer-critical genes, e.g. the coding regions of other cancer-critical genes like Ha-Ras , RB , and PI3KCA do not have non-synonymous coding region SNPs that alter their function in cancer. The next frontier in p53 biology will consist of probing which of these coding region SNPs are moderately or strongly pathogenic and whether they influence cancer risk and the efficacy of cancer therapy. The challenge after that will consist of determining whether we can tailor chemotherapy to correct the defects for each of these variants. Here we review the SNPs in TP53 and MDM2 that show the most significant impact on cancer and other diseases. We also propose avenues for how this information can be used to better inform personalized medicine approaches to cancer and other diseases. [ABSTRACT FROM AUTHOR]

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 Africanspecific 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 S47 cells, including elevated abundance of the low molecular weight thiols coenzyme A (CoA) and glutathione in S47 cells. Importantly, the disparate ferroptosis phenotypes related to the P47S 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. [ABSTRACT FROM AUTHOR]

Approximately half of all human cancers contain mutations in the TP53 tumor suppressor. In addition to mutations, there are single nucleotide polymorphisms (SNPs) in TP53 that can dampen p53 function, and can increase cancer risk and decrease the efficacy of cancer therapy. Approximately 6% of Africans and 1% of African-Americans express a p53 allele with a serine instead of proline at position 47 (Pro47Ser, or S47). The S47 variant is associated with increased breast cancer risk in pre-menopausal African Americans, and in a mouse model for the S47 variant, mice are predisposed to spontaneous cancers. We recently showed that the S47 variant is impaired for p53-mediated apoptosis in response to radiation and some genotoxic agents, particularly cisplatin. Here we identify the mechanism for impaired apoptosis of S47 in response to cisplatin. We show that following cisplatin treatment, the S47 variant shows normal stabilization and serine 15 phosphorylation, but reduced ability to bind to the peptidyl prolyl isomerase PIN1, which controls the mitochondrial localization of p53. This is accompanied by impaired mitochondrial localization of S47, along with decreased induction of cleaved caspase-3. Interestingly, we show that this defect occurs only for cisplatin and not for camptothecin. These findings show that normal tissues may respond differently to genotoxic stress depending upon this TP53 genotype. These data suggest that toxicity to cisplatin may be decreased in S47 individuals, and that this compound may be a superior treatment option for these individuals. [ABSTRACT FROM AUTHOR]

The p53 tumor suppressor continues to be distinguished as the most frequently mutated gene in human cancer. It is widely believed that the ability of p53 to induce senescence and programmed cell death underlies the tumor suppressor functions of p53. However, p53 has a number of other functions that recent data strongly implicate in tumor suppression, particularly with regard to the control of metabolism and ferroptosis (iron- and lipid-peroxide-mediated cell death) by p53. As reviewed here, the roles of p53 in the control of metabolism and ferroptosis are complex. Wild-type (WT) p53 negatively regulates lipid synthesis and glycolysis in normal and tumor cells, and positively regulates oxidative phosphorylation and lipid catabolism. Mutant p53 in tumor cells does the converse, positively regulating lipid synthesis and glycolysis. The role of p53 in ferroptosis is even more complex: in normal tissues, WT p53 appears to positively regulate ferroptosis, and this pathway appears to play a role in the ability of basal, unstressed p53 to suppress tumor initiation and development. In tumors, other regulators of ferroptosis supersede p53's role, and WT p53 appears to play a limited role; instead, mutant p53 sensitizes tumor cells to ferroptosis. By clearly elucidating the roles of WT and mutant p53 in metabolism and ferroptosis, and establishing these roles in tumor suppression, emerging research promises to yield new therapeutic avenues for cancer and metabolic diseases. [ABSTRACT FROM AUTHOR]

TheTP53gene is distinguished as the most frequently mutated gene in cancer. Unlike most cancer-relevant genes, theTP53gene is also distinguished by the existence of coding region polymorphisms that alter p53 sequence, and in some cases, also alter p53 function. A common coding region variant at amino acid 72 of p53 encodes either proline (P72) or arginine (R72). P72 is the ancestral variant and is most common in populations near the equator. The frequency of the R72 variant increases in a linear manner with latitude. To date, why the R72 variant arose in humans and was possibly selected for has remained unclear. Here-in we show that this single nucleotide polymorphism (SNP) influences the phosphorylation of p53 and the transactivation of the key p53 targetCDKN1A(p21) specifically in response to nutrient deprivation, but not in response to conventional cytotoxic agents. Following activation of the kinase AMPK, R72 cells show increased phosphorylation on serine-15 and increased transactivation of the cyclin-dependent kinase inhibitorCDKN1A(p21) and the metabolic response genesPPARGC1B(PGC-1β) andPRKAB2(AMPK-β2). This is accompanied by increased growth arrest and decreased apoptosis in R72 cells compared with P72 cells. The combined data fit best with the hypothesis that the R72 polymorphism confers increased cell survival in response to nutrient deprivation. This differential response to nutrient deprivation may explain part of selection for this SNP at northern latitudes, where nutrient deprivation might have been more frequent. [ABSTRACT FROM PUBLISHER]

In the context of tumor suppression, p53 is an undisputedly critical protein. Functioning primarily as a transcription factor, p53 helps fend off the initiation and progression of tumors by inducing cell cycle arrest, senescence or programmed cell death (apoptosis) in cells at the earliest stages of precancerous development. Compelling evidence, however, suggests that p53 is involved in other aspects of human physiology, including metabolism. Indeed, recent studies suggest that p53 plays a significant role in the development of metabolic diseases, including diabetes, and further that p53's role in metabolism may also be consequential to tumor suppression. Here, we present a review of the literature on the role of p53 in metabolism, diabetes, pancreatic function, glucose homeostasis and insulin resistance. Additionally, we discuss the emerging role of genetic variation in the p53 pathway (single-nucleotide polymorphisms) on the impact of p53 in metabolic disease and diabetes. A better understanding of the relationship between p53, metabolism and diabetes may one day better inform the existing and prospective therapeutic strategies to combat this rapidly growing epidemic. [ABSTRACT FROM AUTHOR]

Summary p53 is well known for its tumor suppressor role, but this protein also has a poorly understood role in the regulation of metabolism. Human studies have implicated a common polymorphism at codon 72 of p53 in diabetic and pre-diabetic phenotypes. To understand this role, we utilized a humanized mouse model of the p53 codon 72 variants and monitored these mice following challenge with a high-fat diet (HFD). Mice with the arginine 72 (R72) variant of p53 developed more-severe obesity and glucose intolerance on a HFD, compared to mice with the proline 72 variant (P72). R72 mice developed insulin resistance, islet hypertrophy, increased infiltration of immune cells, and fatty liver disease. Gene expression analyses and studies with small-molecule inhibitors indicate that the p53 target genes Tnf and Npc1l1 underlie this phenotype. These results shed light on the role of p53 in obesity, metabolism, and inflammation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]