The Codon 72 Polymorphism of p53 Regulates Interaction with NF- B and Transactivation of Genes Involved in Immunity and Inflammation

Fox Chase Cancer Center, W209, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 02/2011; 31(6):1201-13. DOI: 10.1128/MCB.01136-10
Source: PubMed


A common polymorphism at codon 72 in the p53 tumor suppressor gene encodes either proline (P72) or arginine (R72). Several groups have reported that in cultured cells,
this polymorphism influences p53's transcriptional, senescence, and apoptotic functions. However, the impact of this polymorphism
within the context of a living organism is poorly understood. We generated knock-in mice with the P72 and R72 variants and
analyzed the tissues of these mice for apoptosis and transcription. In the thymus, we find that the P72 variant induces increased
apoptosis following ionizing radiation, along with increased transactivation of a subset of p53 target genes, which includes
murine Caspase 4 (also called Caspase 11), which we show is a direct p53 target gene. Interestingly, the majority of genes in this subset have roles in inflammation,
and their promoters contain NF-κB binding sites. We show that caspase 4/11 requires both p53 and NF-κB for full induction
after DNA damage and that the P72 variant shows increased interaction with p65 RelA, a subunit of NF-κB. Consistent with this,
we show that P72 mice have a markedly enhanced response to inflammatory challenge compared to that of R72 mice. Our data indicate
that the codon 72 polymorphism impacts p53's role in inflammation.

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    • "In fact, a majority of gastric cancers bear mutations in the p53 DNA binding domain, thus rendering it transcriptionally inactive [42]. A recent study by Frank et al. reported that codon72 polymorphism of TP53 substantially affects the ability of p53 to cooperate with NF-κB for gene transactivation, particularly in the induction of apoptosis through caspase 4/11 [40]. Together with the present finding that some transcriptional activity of p53 require NF-κB in response to 5-FU, p53 codon 72 polymorphism for its NF-κB binding may be more influential than mutational status of TP53 or protein expression status of p53. "
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    ABSTRACT: Despite of remarkable improvement of postoperative 5-FU-based adjuvant chemotherapy, the relapse rate of gastric cancer patients who undergo curative resection followed by the adjuvant chemotherapy remains substantial. Therefore, it is important to identify prediction markers for the chemotherapeutic efficacy of 5-FU. We recently identified NF-κB as a candidate relapse prediction biomarker in gastric cancer. To evaluate the biological significance of NF-κB in the context of 5-FU-based chemotherapy, we analyzed the NF-κB-dependent biological response upon 5-FU treatment in gastric cancer cell lines. Seven genes induced by 5-FU treatment in an NF-κB-dependent manner were identified, five of which are known p53 targets. Knockdown of RELA, which encodes the p65 subunit of NF-κB, decreased both p53 and p53 target protein levels. In contrast, NF-κB was not affected by TP53 knockdown. We also demonstrated that cell lines bearing Pro/Pro homozygosity in codon72 of p53 exon4, which is important for NF-κB binding to p53, are more resistant to 5-FU than those with Arg/Arg homozygosity. We conclude that NF-κB plays an important role in the response to 5-FU treatment in gastric cancer cell lines, with a possible compensatory function of p53. These results suggest that NF-κB is a potential 5-FU-chemosensitivity prediction marker that may reflect 5-FU-induced stress-response pathways, including p53.
    PLoS ONE 02/2014; 9(2):e90155. DOI:10.1371/journal.pone.0090155 · 3.23 Impact Factor
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    • "All efforts were made to minimize suffering. P72 and R72 Hupki mice used for thymocyte analysis were generated as previously described [15]. These mice were created in C57BL/6–129 background and backcrossed to C57BL/6 for mice for 7 generations. "
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    ABSTRACT: The p53 tumor suppressor gene has a common polymorphism at codon 72 that alters its function. 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); 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. In this report, we address these issues. 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. Notably, the CSF1/CSF1R signaling axis is overexpressed in several epithelial cancers, and there is clinical evidence that this pathway plays a role in radio-resistance of some cancers. We show that cells expressing CSF1 and CSF1R are indeed radio-resistant, and further, that this effect requires p53. 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. Finally, these data may explain the association of the P72 variant and the CSF1/CSF1R pathway with increased senescence and radio-resistance in some epithelial tumor types.
    PLoS ONE 09/2013; 8(9):e74297. DOI:10.1371/journal.pone.0074297 · 3.23 Impact Factor
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    • "Another link between p53 and inflammation is suggested by studies demonstrating the presence of TP53 mutations in areas of rheumatoid arthritis (RA) synovial tissues [66–69]. Frank et al. [47] reported that the Arg72Pro polymorphism of TP53 influences the p53-mediated inflammatory response. The role of p53 in innate immunity and the inflammatory response is now well established [70–72] and, importantly, is evolutionarily conserved [73]. "
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    ABSTRACT: Several lines of evidence indicate that inflammatory processes play a key role in the happening and development of intracranial aneurysm (IA). Recently, polymorphisms in the TP53 gene were shown to be associated with inflammation and inflammatory disease. The aim of this study was to investigate the interactions of miR-34b/c and TP53 Arg72-Pro polymorphisms on the risk of IA in a Chinese population. A total of 590 individuals (including 164 patients with IA and 426 controls) were involved in this study. The polymorphisms (i.e., miR-34b/c rs4938723 and TP53 Arg72-Pro) were genotyped by polymerase chain reaction-restriction fragment length polymorphism assay and DNA sequencing. We found that the CC genotype of miR-34b/c rs4938723 was significantly associated with a decreased risk of IA compared with the TT genotype. Moreover, a significant gene interaction of the carriers with the combined genotypes of miR-34b/c rs4938723CC and TP53 Arg72Pro CG/CC/GG had a decreased risk of IA, compared with those carrying miR-34b/c rs4938723CT/TT+TP53 Arg72Pro GG/CG/CC combined genotypes. These findings suggest that the miR-34b/c rs4938723CC and TP53 Arg72-Pro polymorphisms may be involved in the susceptibility to IA.
    Clinical and Developmental Immunology 07/2012; 2012(1):567586. DOI:10.1155/2012/567586 · 2.93 Impact Factor
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