Modeling gene-environment interactions in oral cavity and esophageal cancers demonstrates a role for the p53 R72P polymorphism in modulating susceptibility

Jayanta Sarkar, Emily Dominguez, Guojun Li, Donna F. Kusewitt, David G. Johnson

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

A large number of epidemiological studies have linked a common single-nucleotide polymorphism (SNP) in the human p53 gene to risk for developing a variety of cancers. This SNP encodes either an arginine or proline at position 72 (R72P) of the p53 protein, which can alter the apoptotic activity of p53 via transcriptional and non-transcriptional mechanisms. This SNP has also been reported to modulate the development of human papilloma virus (HPV)-driven cancers through differential targeting of the p53 variant proteins by the E6 viral oncoprotein. Mouse models for the p53 R72P polymorphism have recently been developed but a role for this SNP in modifying cancer risk in response to viral and chemical carcinogens has yet to be established experimentally. Here, we demonstrate that the p53 R72P polymorphism modulates the hyperprolferative, apoptotic and inflammatory phenotypes caused by expression of the HPV16 E6 and E7 oncoproteins. Moreover, the R72P SNP also modifies the carcinogenic response to the chemical carcinogen 4NQO, in the presence and absence of the HPV16 transgene. Our findings confirm several human epidemiological studies associating the codon 72 proline variant with increased risk for certain cancers but also suggest that there are tissue-specific differences in how the R72P polymorphism influences the response to environmental carcinogens.

Original languageEnglish (US)
Pages (from-to)648-658
Number of pages11
JournalMolecular Carcinogenesis
Volume53
Issue number8
DOIs
StatePublished - Aug 2014

Keywords

  • 4NQO
  • HPV16
  • P53 polymorphism
  • Squamous cell carcinoma

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

MD Anderson CCSG core facilities

  • Research Animal Support Facility

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