p53 Codon 72 Alleles Influence the Response to Anticancer Drugs in Cells from Aged People by Regulating the Cell Cycle Inhibitor p21<sup>WAF1</sup>

Salvioli, Stefano; Bonafè, Massimiliano; Barbi, Cristiana; Storci, Gianluca; Trapassi, Chiara; Tocco, Francesca; Gravina, Silvia; Rossi, Matteo; Tiberi, Luca; Mondello, Chiara; Monti, Daniela; Franceschi, Claudio

doi:10.4161/cc.4.9.1978

Cited by 49 publications

(41 citation statements)

References 28 publications

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“…We find that the P72 variant is associated with increased transactivation of the cyclin-dependent kinase inhibitor p21, along with an increased ability to induce growth arrest and senescence in MEFs; these data mirror the findings on human codon 72 variants of others (5,36). We find that the transforming growth factor ␤ (TGF-␤) superfamily member Gdf15, which is a known p53 target gene, shows increased transactivation in P72 Hupki cells, normal human fibroblasts homozygous for P72, and inducible cell lines containing P72.…”

Section: Discussionsupporting

confidence: 73%

“…1F). Overall, these data were notable because they recapitulate what has been found for the human codon 72 variants in normal fibroblasts (5,36) and therefore support the use of Hupki mice as a valid model in which to investigate functional differences between codon 72 variants. Increased apoptosis in the P72 thymus.…”

Section: Resultsmentioning

confidence: 64%

“…Using genetically engineered inducible cell lines as well as human tumor cell lines homozygous for each variant, we and others have shown that these two forms of p53 differ in their ability to induce growth arrest and apoptosis. Specifically, the P72 variant possesses an increased ability to transactivate p21 and induce growth arrest (5,36,43,46), while the R72 variant demonstrates superior mitochondrial localization in tumor cell lines (8). However, differences in the function of these variants within an intact organism are unclear.…”

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confidence: 99%

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

Frank

Leu

Zhou

et al. 2011

Molecular and Cellular Biology

107

134

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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-B binding sites. We show that caspase 4/11 requires both p53 and NF-B for full induction after DNA damage and that the P72 variant shows increased interaction with p65 RelA, a subunit of NF-B. 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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Section: Discussionsupporting

confidence: 73%

Section: Resultsmentioning

confidence: 64%

mentioning

confidence: 99%

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

Frank

Leu

Zhou

et al. 2011

Molecular and Cellular Biology

107

134

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“…However, in the background of the Eu-myc model of Burkitt's lymphoma, where p53-mediated senescence is known to play a pivotal role, 23 we found that the P72 variant, which possesses superior ability to induce senescence in human and murine cells, 6 conferred increased survival in this model. 8 The combined data suggest that the codon 72 polymorphism is likely to influence apoptosis and tumor suppression in a tissue-and/or tumor-specific manner; this may explain the controversial findings in human studies.…”

confidence: 90%

“…Experimental studies in cell lines suggest that the P72 variant possesses increased ability to induce growth arrest and senescence due to increased ability to transactivate p21/ waf1. [6][7][8] Conversely, the R72 variant possesses increased ability to induce apoptosis, In our investigations on the biology of the p53 codon 72 polymorphism, we made use of the humanized knock-in model for p53 (Humanized p53 knock-in or Hupki). In this model, the murine p53 sequences from exon 4 through exon 9 have been replaced with the corresponding human p53 segment.…”

Section: Introductionmentioning

confidence: 99%

Tissue-specific apoptotic effects of the p53 codon 72 polymorphism in a mouse model

Azzam¹,

Frank²,

Hollstein³

et al. 2011

Cell Cycle

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Currently there are several dozen human polymorphisms that have been loosely associated with cancer risk. Correlating such variants 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 large sample sizes for analysis. Such difficulties can be circumvented with the establishment of mouse models for human variants. Recently, several groups have modeled human cancer susceptibility polymorphisms in the mouse. Remarkably, in each case these mouse models have accurately reflected human phenotypes, and clarified the contribution of these variants to cancer risk. We recently reported on a mouse model for the codon 72 polymorphism in p53, and found that this polymorphism regulates the ability to cooperate with NFκB and induce apoptosis. Here-in we present evidence that this polymorphism impacts the apoptotic function of p53 in a tissue-specific manner; such tissue-specific effects of polymorphic variants represent an added challenge to human cancer risk association studies. The data presented here support the premise that modeling human polymorphisms in the mouse represents a powerful tool to assess the impact of these variants on cancer risk, progression and therapy.

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Association between TP53 R249S mutation and polymorphisms in TP53 intron 1 in hepatocellular carcinoma

Ortiz-Cuarán

Cox

Villar

et al. 2013

Genes Chromosomes & Cancer

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Over 100 single nucleotide polymorphisms (SNP) are validated in the TP53 tumor suppressor gene. They define haplotypes, which may differ in their activities. Therefore, mutation in cancer may occur at different rates depending upon haplotypes. However, these associations may be masked by differences in mutations types and causes of mutagenesis. We have analyzed the associations between 19 SNPs spanning the TP53 locus and a single specific aflatoxin-induced TP53 mutation (R249S) in 85 in hepatocellular carcinoma cases and 132 controls from Thailand. An association with R249S mutation (P = 0.007) was observed for a combination of two SNPs (rs17882227 and rs8064946) in a linkage disequilibrium block extending from upstream of exon 1 to the first half of intron 1. This domain contains two coding sequences overlapping with TP53 (WRAP53 and Hp53int1) suggesting that sequences in TP53 intron 1 encode transcripts that may modulate R249S mutation rate in HCC.

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p53 Codon 72 Alleles Influence the Response to Anticancer Drugs in Cells from Aged People by Regulating the Cell Cycle Inhibitor p21^WAF1

Cited by 49 publications

References 28 publications

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

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

Tissue-specific apoptotic effects of the p53 codon 72 polymorphism in a mouse model

Association between TP53 R249S mutation and polymorphisms in TP53 intron 1 in hepatocellular carcinoma

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p53 Codon 72 Alleles Influence the Response to Anticancer Drugs in Cells from Aged People by Regulating the Cell Cycle Inhibitor p21WAF1

Cited by 49 publications

References 28 publications

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

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

Tissue-specific apoptotic effects of the p53 codon 72 polymorphism in a mouse model

Association between TP53 R249S mutation and polymorphisms in TP53 intron 1 in hepatocellular carcinoma

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p53 Codon 72 Alleles Influence the Response to Anticancer Drugs in Cells from Aged People by Regulating the Cell Cycle Inhibitor p21^WAF1