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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...
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...
Cancer is special among genetic disorders in two major ways: first, cancer is a disease of the most basic of cellular functions, such as cell proliferation, differentiation, and the maintenance of genomic integrity. Second, in contrast to most genetic disorders that are mediated by germline (hereditary) mutations, cancer is largely a somatic disease. Here we show that these two traits are not detached and that it is the somatic nature of cancer that allows it to affect the most basic of cellular functions. We begin by demonstrating that cancer genes are both more functionally central (as measured by their patterns of expression and protein interaction) and more evolutionarily constrained than non-cancer genetic disease genes. We then compare genes that are only modified somatically in cancer (hereinafter referred to as “somatic cancer genes”) to those that can also be modified in a hereditary manner, contributing to cancer development (hereinafter referred to as “hereditary cancer genes”). We show that both somatic and hereditary cancer genes are much more functionally central than genes contributing to non-cancer genetic disorders. At the same time, hereditary cancer genes are only as constrained as non-cancer hereditary disease genes, while somatic cancer genes tend to be much more constrained in evolution. Thus, it appears that it is the somatic nature of cancer that allows it to modify the most constrained genes and, therefore, affect the most basic of cellular functions.
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