Tissue-specific apoptotic effects of the p53 codon 72 polymorphism in a mouse model

Abstract

Currently there are several dozen human polymorphisms that have been loosely associated with cancer risk. Correlating such variants with cancer risk has been challenging, primarily due to factors such as genetic heterogeneity, contributions of diet and environmental factors, and the difficulty in obtaining large sample sizes for analysis. Such difficulties can be circumvented with the establishment of mouse models for human variants. Recently, several groups have modeled human cancer susceptibility polymorphisms in the mouse. Remarkably, in each case these mouse models have accurately reflected human phenotypes, and clarified the contribution of these variants to cancer risk. We recently reported on a mouse model for the codon 72 polymorphism in p53, and found that this polymorphism regulates the ability to cooperate with NFκB and induce apoptosis. Here-in we present evidence that this polymorphism impacts the apoptotic function of p53 in a tissue-specific manner; such tissue-specific effects of polymorphic variants represent an added challenge to human cancer risk association studies. The data presented here support the premise that modeling human polymorphisms in the mouse represents a powerful tool to assess the impact of these variants on cancer risk, progression and therapy.

Association between p53 Gene Variants and Oral Cancer Susceptibility in Population from Gujarat, West India

“…This effect of Arg72Pro polymorphism may inhibit p53 function in vitro but whether this effect also occur in vivo remains to be determined. Recently, studies on mouse model indicate that the Arg-72 variant induces increased apoptosis in mouse embryo fibroblast (MEF) and in the small intestines of mice along with decreased apoptosis in the thymus compared to Pro-72 (Zhu et al, 2010;Azzam et al, 2011). Thus, there is tissue specific influence of Arg72Pro polymorphism on apoptosis.…”

TP53 Gene Polymorphisms in Cancer Risk: The Modulating Effect of Ageing, Ethnicity and TP53 Somatic Abnormalities

“…Aside from the abovementioned data, it was recently established that the TP53 rs1042522 polymorphism impacts the apoptotic function of p53 in a tissue-specific manner. Specifically, p53Pro protein more effectively activates programmed cell death in thymus , whereas in the small intestine, apoptosis is significantly higher in G-expressing cells (Azzam et al, 2011;. Interestingly, in the spleen, there was no difference in the induction of apoptosis between rs1042522 variants (Azzam et al, 2011).…”

“…Simply stated, p53Pro protein seems to be the best inductor of apoptosis in the extrinsic pathway. This also results from the fact that p53Pro, but not p53Arg, along with NF-kB, transactivates caspase 4/11, an important component of the extrinsic pathway in apoptosis induction (Azzam et al, 2011;Frank et al, 2011). Aside from the abovementioned data, it was recently established that the TP53 rs1042522 polymorphism impacts the apoptotic function of p53 in a tissue-specific manner.…”

“…Specifically, p53Pro protein more effectively activates programmed cell death in thymus , whereas in the small intestine, apoptosis is significantly higher in G-expressing cells (Azzam et al, 2011;. Interestingly, in the spleen, there was no difference in the induction of apoptosis between rs1042522 variants (Azzam et al, 2011). Taken together, the tumorsuppressing function of p53 is considerably modified by TP53 rs1042522 polymorphism, while the effect of p53 allelic variants on tumor growth, mainly manifested in apoptosis regulation, depends on the genetic and tissue-specific background.…”

“…The significant heterogeneity of the associative value of TP53 polymorphisms, especially rs1042522 variation, among human cancers is most likely explained by specific p53 inducible functionality essentially depending on ethnicity-related genetic background and environmental exposure, tissue and age specificity (Azzam et al, 2011;Chung et al, 2010;Donehower, 2006;Francisco et al, 2010;van Heemst et al, 2005). The complex of lifestyle endo-and exogenous factors of each ethnic group, the proportion of which increases with age, may dramatically modulate the contribution of TP53 polymorphisms to cancer risk through, for example, genotoxic effects and epigenetic modifications of the TP53 gene structure.…”