The codon 72 polymorphism of p53 regulates interaction with NF-{kappa}B and transactivation of genes involved in immunity and inflammation.
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.
Fox Chase Cancer Center, W209, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Amanda K
AK
Frank
Julia I-Ju
JI
Leu
Yan
Y
Zhou
Karthik
K
Devarajan
Tatiana
T
Nedelko
Andres
A
Klein-Szanto
Monica
M
Hollstein
Maureen E
ME
Murphy
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000235:genetics; D053471:Caspases, Initiator; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D055879:Gene Knock-In Techniques; D007109:Immunity; D007249:Inflammation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D011110:Polymorphism, Genetic; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics
D016328:NF-kappa B; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D018631:ras Proteins
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