The codon 72 polymorphism of p53 influences cell fate through cytokine expression and signaling

Gregory Albert Azzam

doi:10.17918/00000461

The p53 tumor suppressor gene has a common polymorphism at codon 72 that alters its function. Correlating codon 72 variations 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 sufficiently large sample sizes for statistical analysis. Such difficulties can be circumvented with the establishment of mouse models for human variants. We previously reported that the proline 72 polymorphic variant of p53 (P72) demonstrates increased ability to transactivate a subset of genes, relative to arginine 72 (R72) in a Humanized-p53 Knock-In (Hupki) mouse model. One of these genes is macrophage colony stimulating factor (CSF1). At present, the mechanism(s) underlying the increased transcriptional activity of P72 toward genes like CSF1 have not been completely elucidated. Additionally, the consequences of increased transcription of genes like CSF1 by the P72 variant to the downstream p53 pathway are unknown. Here-in we present evidence that this polymorphism impacts the apoptotic function of p53 in a tissue-specific manner and suggest that these differences may be due at least partially to cytokine signaling. We show that the CSF1 gene contains a conserved binding site for p53, and interestingly that the P72 variant shows increased ability to bind to this site. Moreover, we show that increased CSF1/CSF1R signaling in P72 cells feeds back on the p53 pathway to enhance p53 phosphorylation, levels, and transactivation of target genes, particularly the cyclin-dependent kinase inhibitor p21 (CDKN1A). This leads to an increase in p53-mediated growth arrest, along with a concomitant decrease in apoptosis. These combined data are the first to implicate the CSF1/CSF1R pathway in the decision between p53-mediated growth arrest and apoptosis. They are also the first to highlight a cytokine as influential in cell fate determined by p53 in epithelial cells. Transactivation by p53 of cytokines like CSF1 and signaling events that follow may help to explain tissue-specific differences in apoptosis observed for p53 polymorphic variants following gamma irradiation and other stresses. These data also suggest that the status of the codon 72 polymorphism of p53 may influence efficacy of chemo- or radiation therapy.

The codon 72 polymorphism of p53 influences cell fate through cytokine expression and signaling

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The codon 72 polymorphism of p53 influences cell fate through cytokine expression and signaling

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