title: Modeling gene-environment interactions in oral cavity and esophageal cancers demonstrates a role for the p53 R72P polymorphism in modulating susceptibility.
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.
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Sarkar
authors.forename: Emily
authors.initials: E
authors.lastname: Dominguez
authors.forename: Guojun
authors.initials: G
authors.lastname: Li
authors.forename: Donna F
authors.initials: DF
authors.lastname: Kusewitt
authors.forename: David G
authors.initials: DG
authors.lastname: Johnson
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002478:Cells, Cultured; D004279:DNA, Viral / Q000235:genetics; D004938:Esophageal Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D059647:Gene-Environment Interaction; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009062:Mouth Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009856:Oncogene Proteins, Viral / Q000502:physiology; D027383:Papillomaviridae / Q000235:genetics; D050725:Papillomavirus E7 Proteins / Q000502:physiology; D030361:Papillomavirus Infections / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D002273:Carcinogens; D004279:DNA, Viral; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16; D015112:4-Nitroquinoline-1-oxide
keywords: 4NQO; HPV16; p53 polymorphism; squamous cell carcinoma