Article

The codon 72 polymorphism of p53 regulates interaction with NF-κB 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: 5.04). 02/2011; 31(6):1201-13. DOI: 10.1128/MCB.01136-10
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Amanda K Frank, Aug 25, 2015
0 Followers
 · 
101 Views
  • Source
    • "At present, the most significant TP53 polymorphisms are undoubtedly rs1042522 (Ex4 + 119C > G: C and G alleles), rs1625895 (IVS6 + 62A > G: A and G alleles), and rs17878362 (16 bp duplication in intron 3: A1, nonduplicated allele and A2, duplicated allele). Different functional abilities concerning activation of cell processes, such as transactivation, apoptosis, cell cycle arrest and senescence, DNA repair, removal of micronuclei, and maintenance of genomic stability, have been observed for the p53 protein encoded by the TP53 alleles, rs17878362, rs1042522, and rs1625895 (Whibley et al., 2009; Litviakov et al., 2010; Frank et al., 2011). "
    DNA and Cell Biology 01/2012; 31(3):306-316. · 1.99 Impact Factor
  • Source
    • "At present, the most significant TP53 polymorphisms are undoubtedly rs1042522 (Ex4 + 119C > G: C and G alleles), rs1625895 (IVS6 + 62A > G: A and G alleles), and rs17878362 (16 bp duplication in intron 3: A1, nonduplicated allele and A2, duplicated allele). Different functional abilities concerning activation of cell processes, such as transactivation, apoptosis, cell cycle arrest and senescence, DNA repair, removal of micronuclei, and maintenance of genomic stability, have been observed for the p53 protein encoded by the TP53 alleles, rs17878362, rs1042522, and rs1625895 (Whibley et al., 2009; Litviakov et al., 2010; Frank et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the potential for gene-gene interaction effects in sporadic breast cancer (BC) risk, we studied combinations of the fibroblast growth factor receptor 2 (FGFR2) rs1219648 and tumor protein 53 (TP53) rs1042522, rs1625895, and rs17878362 polymorphisms in BC patients (n=388) and healthy persons (n=275). In addition to a single-locus effect manifested by the association of FGFR2 rs1219648 and TP53 rs1042522 polymorphisms with high BC risk, depending on menopause status (0.001<p<0.05), we showed a highly significant cooperation between the examined polymorphisms in FGFR2 and TP53 in the determination of susceptibility to the disease. Indeed, we found that combinations of FGFR2 minor and TP53 major genotypes were associated with a high risk of BC, particularly in the postmenopausal period (0.01<p<0.05). In contrast, combinations of the FGFR2 and TP53 major genotypes had a protective effect against BC, especially in premenopausal women (0.001<p<0.01). Of note, all observations were estrogen receptor (ER) dependent. The significant crosstalk between FGFR2 and TP53 polymorphisms was also confirmed by multifactor dimensionality reduction and ordered combinatorial partitioning approaches (0.001<p<0.05). Taken together, data from the present study demonstrate the age- and ER-specific interplay between TP53 and FGFR2 in BC.
    DNA and cell biology 08/2011; 31(3):306-16. DOI:10.1089/dna.2011.1351 · 1.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Numerous observations indicate a strong link between chronic inflammation and cancer. This link is supported by substantial experimental evidence indicating mutual negative regulation of NF-κB, the major regulator of inflammation, and p53, the major tumor suppressor. This antagonistic relationship reflects the opposite principles of the physiological responses driven by these transcription factors, which act as sensors and mediators of intrinsic and extrinsic cell stresses, respectively. Constitutive activation of NF-κB, the underlying cause of chronic inflammation, is a common acquired characteristic of tumors. A variety of experimental methods have been used to demonstrate that constitutive activation of NF-κB reduces the tumor suppressor activity of p53, thereby creating permissive conditions for dominant oncogene-mediated transformation. Loss of p53 activity is also a characteristic of the majority of tumors and results in unleashed inflammatory responses due to loss of p53-mediated NF-κB suppression. On the other hand, in natural or pharmacological situations of enforced p53 activation, NF-κB activity, inflammation, and immune responses are reduced, resulting in different pathologies. It is likely that the chronic inflammation that is commonly acquired in various tissues of older mammals leads to general suppression of p53 function, which would explain the increased risk of cancer observed in aging animals and humans. Although the molecular mechanisms underlying reciprocal negative regulation of p53 and NF-κB remain to be deciphered, this phenomenon has important implications for pharmacological prevention of cancer and aging and for new approaches to control inflammation.
    Genes & cancer 04/2011; 2(4):503-16. DOI:10.1177/1947601911409747
Show more