Document Detail


The codon 72 polymorphism of p53 regulates interaction with NF-{kappa}B and transactivation of genes involved in immunity and inflammation.
MedLine Citation:
PMID:  21245379     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Amanda K Frank; Julia I-Ju Leu; Yan Zhou; Karthik Devarajan; Tatiana Nedelko; Andres Klein-Szanto; Monica Hollstein; Maureen E Murphy
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-01-18
Journal Detail:
Title:  Molecular and cellular biology     Volume:  31     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-02-25     Completed Date:  2011-04-21     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1201-13     Citation Subset:  IM    
Affiliation:
Fox Chase Cancer Center, W209, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis
Caspases / genetics
Cells, Cultured
Fibroblasts / metabolism
Gene Knock-In Techniques
Immunity
Inflammation / genetics
Mice
Mice, Inbred C57BL
NF-kappa B / immunology,  metabolism*
Polymorphism, Genetic*
Thymus Gland / cytology,  metabolism
Transcription Factor RelA / metabolism
Transcriptional Activation*
Tumor Suppressor Protein p53 / genetics*,  immunology,  metabolism*
ras Proteins / genetics
Grant Support
ID/Acronym/Agency:
R01 CA102184-06/CA/NCI NIH HHS; R01 CA102184-07/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/NF-kappa B; 0/Transcription Factor RelA; 0/Tumor Suppressor Protein p53; EC 3.4.22.-/Casp11 protein, mouse; EC 3.4.22.-/Caspases; EC 3.6.5.2/ras Proteins
Comments/Corrections

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