Polymorphic variants in the p53 pathway

Murphy, Maureen E.

doi:10.1038/sj.cdd.4401907

Cited by 87 publications

(82 citation statements)

References 41 publications

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“…It was proposed that the high levels of MDM2 resulting from the G-allele attenuate the p53 stress response, resulting in a higher mutation rate, poorer DNA repair processes, reduced apoptosis, and senescence, leading to faster and more frequent tumor formation (1). Support for the model has come from the association of MDM2 SNP309 with differences in the onset of, or the risk for, cancer, as well as survival (2,3,18). For example, earlier ages of onset associated with individuals possessing the G-allele have been demonstrated in softtissue sarcomas (1,19,20), lymphoma (21), leukemia (22), melanoma (23), head, neck, and oral squamous cell carcinomas (24,25), and cancers of the colon (26), breast (21,27,28), bladder (29), ovary (30), brain (31), and liver (32).…”

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confidence: 99%

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

Atwal

Kirchhoff

Bond

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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A large body of evidence strongly suggests that the p53 tumor suppressor pathway is central in reducing cancer frequency in vertebrates. The protein product of the haploinsufficient mouse double minute 2 (MDM2) oncogene binds to and inhibits the p53 protein. Recent studies of human genetic variants in p53 and MDM2 have shown that single nucleotide polymorphisms (SNPs) can affect p53 signaling, confer cancer risk, and suggest that the pathway is under evolutionary selective pressure ( 1 – 4 ). In this report, we analyze the haplotype structure of MDM4, a structural homolog of MDM2, in several different human populations. Unusual patterns of linkage disequilibrium (LD) in the haplotype distribution of MDM4 indicate the presence of candidate SNPs that may also modify the efficacy of the p53 pathway. Association studies in 5 different patient populations reveal that these SNPs in MDM4 confer an increased risk for, or early onset of, human breast and ovarian cancers in Ashkenazi Jewish and European cohorts, respectively. This report not only implicates MDM4 as a key regulator of tumorigenesis in the human breast and ovary, but also exploits for the first time evolutionary driven linkage disequilibrium as a means to select SNPs of p53 pathway genes that might be clinically relevant.

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confidence: 99%

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

Atwal

Kirchhoff

Bond

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…This region is required for the growth suppression and apoptosis mediated by p53 but not for cell cycle arrest [6]. Arg72 form of p53 is a more efficient inducer of apoptosis than Pro72, and thus may increase the responsiveness to chemotherapy [7][8][9]. Pro72 is more efficient in transactivating p21 and inducing cell cycle arrest [10].…”

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confidence: 99%

Association of EGF and p53 gene polymorphisms and colorectal cancer risk in the Slovak population

et al. 2014

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AbstractDuring the transformation process single nucleotide polymorphisms (SNPs) of key genes, such as p53 Arg72Pro or EGF A61G, may mediate various cellular processes. These variants may be associated with colorectal cancer risk (CRC), but conflicting findings have been reported. The purpose of this study was to determine the association of the SNPs in 5′ UTR of EGF A61G and p53 Arg72Pro and CRC in the Slovak population. The present case-control study was carried out in 173 confirmed CRC patients and 303 healthy subjects. Genotyping was performed by PCR-RFLP methods. Significant association was observed between age and CRC risk (p=0.001). Lower CRC risk was seen in younger patients carrying genotype p53 Arg72Pro (0.14; 95% CI 0.02–0.99, p=0.049). Gender-stratified analysis showed a significant inverse association of the polymorphism EGF G61G with CRC risk (0.48; 95% CI 0.2–0.9, p=0.04) only in male patients. Tumour site genotype distribution revealed that female patients with localized colon cancer were significantly associated with p53 Pro72Pro genotype (4.0; 95% CI 1.27–12.7, p=0.04) whereas the cancer of rectosigmoid junction was associated with the EGF G61G genotype (4.5; 95% CI 1.2–16.97, p=0.02). Combination of p53 Arg72Pro or EGF A61G polymorphisms were not associated with CRC risk by using logistic regression.

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“…Functional SNPs in the human genome have been identified in both the p53 and the MDM2 genes (4). In the p53 gene, a SNP (codon 72) results in the change of a proline residue to an arginine at codon 72 of the p53 protein (p53-Pro and p53-Arg, respectively).…”

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confidence: 99%

Haplotype structure and selection of the MDM2 oncogene in humans

Atwal

Bond

Metsuyanim³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The MDM2 protein is an ubiquitin ligase that plays a critical role in regulating the levels and activity of the p53 protein, which is a central tumor suppressor. A SNP in the human MDM2 gene (SNP309 T/G) occurs at frequencies dependent on demographic history and has been shown to have important differential effects on the activity of the MDM2 and p53 proteins and to associate with altered risk for the development of several cancers. In this report, the haplotype structure of the MDM2 gene is determined by using 14 different SNPs across the gene from three different population samples: Caucasians, African Americans, and the Ashkenazi Jewish ethnic group. The results presented in this report indicate that there is a substantially reduced variability of the deleterious SNP309 G allele haplotype in all three populations studied, whereas multiple common T allele haplotypes were found in all three populations. This observation, coupled with the relatively high frequency of the G allele haplotype in both and Caucasian and Ashkenazi Jewish population data sets, suggests that this haplotype could have undergone a recent positive selection sweep. An entropy-based selection test is presented that explicitly takes into account the correlations between different SNPs, and the analysis of MDM2 reveals a significant departure from the standard assumptions of selective neutrality.cancer ͉ p53 ͉ population genetics ͉ SNP ͉ entropy I n response to a wide variety of stresses, such as DNA damage or oncogene activation, the p53 tumor suppressor protein is activated and initiates a transcriptional program leading to cell cycle arrest, cell senescence or apoptosis (1). This eliminates clones of cells that have acquired mutations, which arise at a high frequency when DNA replication or the cell cycle proceeds under stress. When the p53 gene is mutated in either the germ line or in a somatic cell, many types of cancers can arise (2). The p53 protein is regulated by a ubiquitin ligase, the MDM2 protein, which binds to p53, blocking its function as a transcription factor, and polyubiquitinates the p53 protein sending it to the proteiosome for degradation (3). The MDM2 gene in turn is positively regulated by p53-mediated transcription, setting up an autoregulatory loop that keeps both proteins at moderate levels. Stress responses perturb this feedback loop, which leads to the initiation of p53-dependent apoptosis.Functional SNPs in the human genome have been identified in both the p53 and the MDM2 genes (4). In the p53 gene, a SNP (codon 72) results in the change of a proline residue to an arginine at codon 72 of the p53 protein (p53-Pro and p53-Arg, respectively). Multiple groups have shown that p53-Pro is weaker than p53-Arg in its ability to both suppress cellular transformation and induce apoptosis in cell culture (5-8), and can associate with an earlier onset of tumor formation and a poorer tumor response to chemotherapy in humans (7, 9, 10). In the MDM2 gene, a SNP (SNP309) results in a nucleotide change from the wild-type thymine (T...

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Polymorphic variants in the p53 pathway

Cited by 87 publications

References 41 publications

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

Association of EGF and p53 gene polymorphisms and colorectal cancer risk in the Slovak population

Haplotype structure and selection of the MDM2 oncogene in humans

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