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The codon 72 polymorphism of p53 influences cell fate following nutrient deprivation.

ABSTRACT: The TP53 gene is distinguished as the most frequently mutated gene in cancer. Unlike most cancer-relevant genes, the TP53 gene 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 target CDKN1A (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 inhibitor CDKN1A (p21) and the metabolic response genes PPARGC1B (PGC-1?) and PRKAB2 (AMPK-?2). 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.

SUBMITTER: Kung CP

PROVIDER: S-EPMC5639853 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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The codon 72 polymorphism of p53 influences cell fate following nutrient deprivation.

Kung Che-Pei CP Liu Qin Q Murphy Maureen E ME

Cancer biology & therapy 20170505 7

The TP53 gene is distinguished as the most frequently mutated gene in cancer. Unlike most cancer-relevant genes, the TP53 gene 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 li ...[more]

PMID: 28475405

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Project description:Squamous cell carcinoma of the penis is a rare but often aggressive disease. A large proportion of penile cancers are associated with HPV infection, mainly with HPV high-risk subtypes 16 and 18. From other HPV-related malignancies a link between a functional SNP in the p53 gene (rs1042522, p.Arg72Pro) and a higher disease risk in the presence of HPV is documented. The p53 p.Arg72 variant was described as a risk factor for developing a malignancy in combination with the presence of HPV as the p.72Arg variant is more prone to HPV E6 protein-mediated degradation than the p.72Pro variant. For penile carcinoma there are only sparse data available on this topic. We therefore analyzed the distribution of this p53 codon 72 SNP in a cohort of 107 penile cancer patients and a healthy control group (n=194) using Restriction Fragment Length Polymorphism (RFLP) analysis. After DNA isolation a PCR amplicon including the variant nucleotide was generated. Based on the variant nucleotide this amplicon can be cleaved into two parts or remain unaffected by a restriction enzyme. Subsequent electrophoresis allowed the discrimination of SNP alleles in the investigated sample. Comparison of the allelic variants revealed no significant differences in the distribution of this SNP between cases and controls (p=0,622). There was also no difference in SNP distribution between cases with/without HPV infection (p=0,558) or histologic variants (p=0.339). In order to strengthen the impact of our data we performed a combined analysis of all published data on this topic with our results. This ended up in SNP distribution data from 177 cases and 1149 controls. Overall, there were also no significant differences in the allelic distribution of the p53 codon 72 SNP between either cases and controls (p=0,914) or HPV-positive and HPV-negative cases (p=0,486). From this most comprehensive data available to date we conclude that there is no influence of the p53 codon 72 SNP on the risk of development of penile carcinoma in Caucasians even in the presence of HPV.

Dataset Information

The codon 72 polymorphism of p53 influences cell fate following nutrient deprivation.

Publications

The codon 72 polymorphism of p53 influences cell fate following nutrient deprivation.

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