Individuals exposed to the same environmental agent often respond differently due to additional factors such as genetics. Therefore, determining how human sequence variations (polymorphisms) influence the response to environmental exposures is key to understanding individual variability in disease susceptibility. The human p53 gene, which plays a critical role in the response to many cellular stresses, contains a common polymorphism that results in either an arginine (R) or proline (P) residue at position 72 of the p53 protein. Numerous epidemiological studies have associated this polymorphism with risk for developing various cancers and other diseases. However, different genotypes are associated with a predisposition for developing different cancers and in some cases there is conflicting data. Some laboratory studies suggest that the two p53 variants differ in their abilities to activate certain target genes while other studies suggest that the variants differ in their ability to induce apoptosis through a transcription-independent mechanism. Moreover, this polymorphism may affect the gain-of-function ability of mutant p53. A major problem with the interpretation of these functional studies is that all were done using artificial in vitro conditions and thus there is a critical need to model the R72P polymorphism in a way that is more physiologically relevant. This application is based on the hypothesis that the human p53 R72P polymorphism can be modeled in the mouse and that these models can be important tools for basic and translational research. Mouse models have been developed to study the role of specific mutations and sites of modification on p53, but no mouse model has been developed to study the R72P polymorphism. This may be because amino acid 72 is located in a region of human p53 that lacks homology to murine p53. To overcome this problem, we have used two different approaches to develop "humanized" mouse models for the p53 R72P polymorphism. Experiments proposed in this application will validate these mouse models with a focus on determining how the R72P polymorphism modulates apoptosis and skin cancer development. The long-term objective of this proposal is to use data from these mouse model studies to develop and test new hypothesis on the role of this p53 polymorphism in human health and disease.

Public Health Relevance

Determining how small variations in the human genome (polymorphisms) influence the response to environmental exposures is key to understanding individual variability in disease susceptibility. Epidemiological studies suggest that a single nucleotide polymorphism (SNP) in the human p53 gene affects an individual's chances of developing various cancers but the underlying mechanism for this is not understood. This proposal seeks to use novel mouse models to study how this common p53 SNP modulates the development of human cancer and other environmentally related diseases.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mcallister, Kimberly A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Bruning, Oskar; Rodenburg, Wendy; van Oostrom, Conny T et al. (2014) A range finding protocol to support design for transcriptomics experimentation: examples of in-vitro and in-vivo murine UV exposure. PLoS One 9:e97089
Sarkar, Jayanta; Dominguez, Emily; Li, Guojun et al. (2014) Modeling gene-environment interactions in oral cavity and esophageal cancers demonstrates a role for the p53 R72P polymorphism in modulating susceptibility. Mol Carcinog 53:648-58
Perez, Carlos J; Rundhaug, Joyce E; Johnson, David G et al. (2014) Slug expression in mouse skin and skin tumors is not regulated by p53. J Invest Dermatol 134:566-8
Yu, Hongping; Sturgis, Erich M; Liu, Zhensheng et al. (2012) Modifying effect of MDM4 variants on risk of HPV16-associated squamous cell carcinoma of oropharynx. Cancer 118:1684-92
Yu, Hongping; Wang, Li-E; Liu, Zhensheng et al. (2011) Polymorphisms of MDM4 and risk of squamous cell carcinoma of the head and neck. Pharmacogenet Genomics 21:388-96
Zhang, Yang; Sturgis, Erich M; Zafereo, Mark E et al. (2011) p14ARF genetic polymorphisms and susceptibility to second primary malignancy in patients with index squamous cell carcinoma of the head and neck. Cancer 117:1227-35
Yu, Hongping; Huang, Yu-jing; Liu, Zhensheng et al. (2011) Effects of MDM2 promoter polymorphisms and p53 codon 72 polymorphism on risk and age at onset of squamous cell carcinoma of the head and neck. Mol Carcinog 50:697-706
Post, Sean M; Quintás-Cardama, Alfonso; Pant, Vinod et al. (2010) A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. Cancer Cell 18:220-30
Zhu, Feng; Dolle, Martijn E T; Berton, Thomas R et al. (2010) Mouse models for the p53 R72P polymorphism mimic human phenotypes. Cancer Res 70:5851-9