p53 may affect susceptibility to cancer and other diseases
By Ashley Godfrey
In her seminar, “Adventures in polymorphisms and p53 function,” Wistar Institute professor Maureen Murphy, Ph.D., (http://www.wistar.org/lab/maureen-murphy-phd) discussed her research on polymorphisms in the p53 protein. Murphy’s talk May 7 at NIEHS was hosted by Intramural Research Training Award Fellow Kin Chan, Ph.D., as part of the NIEHS Laboratory of Molecular Genetics (LMG) Fellows Invited Lecture Series.
“What’s especially exciting about Murphy’s work is her use of a humanized p53 knock-in mouse model to examine the effects of polymorphisms in p53 on multiple levels,” explained Chan. “As Maureen showed during her talk, two different alleles at amino acid 72 can give rise to very different health outcomes, as reflected by differences in susceptibility to diabetes, in effectiveness of immune function, and in female fertility.”
The p53 tumor suppressor
The p53 protein is crucial in multicellular organisms, where it regulates the cell cycle and is therefore involved in cancer prevention. As Murphy indicated in her talk, mutations in p53 are present in about 60 percent of all human tumors.
Research from Murphy’s lab indicates that p53 suppresses tumor development, in part, through its ability to induce apoptosis, or cell death. In cells where DNA damage has occurred or where there is unscheduled cell proliferation, as there often is during cancer development, the p53 protein becomes stabilized and induces apoptosis in response to these and other cellular stresses.
Murphy and her lab are particularly interested in two different coding region polymorphisms, or single amino acid variants, in p53 and the impact these polymorphisms may have on the protein’s ability to induce apoptosis. The first is more common in African-Americans than white Americans, substituting a proline residue at codon 72 (P72) for an arginine (R72), and the second is more rare, substituting a serine residue at codon 47 (S47) for a proline (P47). The S47 variant has only been found in the African-American population. Interestingly, the codon 72 variants also vary with geographic location. About 40 percent of people who live near the equator are homozygous for P72 but, higher up in latitude, the percentage drops and more people have the R72 variant.
“Since the P72 and S47 variants are more common in African-Americans this may help to explain ethnic disease disparities,” stated Murphy.
Using a unique mouse model to study different health outcomes
In order to understand how the codon 72 polymorphism could affect the function of p53, Murphy and her collaborators have created the first mouse model for this p53 polymorphism. Since the mouse p53 protein does not have this polymorphism, the knock-in mouse contains a humanized version of p53, encoding either the P72 or R72 variants. Murphy’s research with this mouse model has shown that mice containing the P72 and R72 variants have significantly altered levels of apoptosis in different tissues.
By looking at the different gene transcriptional responses between the two variants, Murphy has shown that P72 and R72 respond dramatically differently to innate immunity stress. This difference is regulated by a subset of genes known to control the inflammatory response, including some of the NF-kB target genes, which are better activated by the P72 variant.
“If P72 has a better response with innate immunity, then it might make sense why this variant is selected for near the equator where malaria and other infections are more common,” explained Murphy. In contrast, the R72 variant in people seems to be selected for in colder climates, and Murphy’s data suggests that R72 mice tolerate a diet rich in fat and sugar better, while P72 mice tend to develop diabetes on this regimen, which may explain the higher risk for diabetes in African-American populations.
Murphy concluded her talk with a brief look at her research on the other, less common p53 polymorphism. She has found that the S47 variant has impaired phosphorylation, which leads to decreased apoptosis. A better understanding of the role of these variants in disease should lead to improved diagnosis and treatment.
(Ashley Godfrey, Ph.D., is a postdoctoral fellow in the Molecular and Genetic Epidemiology Group in the NIEHS Laboratory of Molecular Carcinogenesis.)