A Single Nucleotide Polymorphism in the MDM2 Promoter Attenuates the p53 Tumor Suppressor Pathway and Accelerates Tumor Formation in Humans

Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA.
Cell (Impact Factor: 32.24). 12/2004; 119(5):591-602. DOI: 10.1016/j.cell.2004.11.022
Source: PubMed


The tumor suppressor p53 gene is mutated in minimally half of all cancers. It is therefore reasonable to assume that naturally occurring polymorphic genetic variants in the p53 stress response pathway might determine an individual's susceptibility to cancer. A central node in the p53 pathway is the MDM2 protein, a direct negative regulator of p53. In this report, a single nucleotide polymorphism (SNP309) is found in the MDM2 promoter and is shown to increase the affinity of the transcriptional activator Sp1, resulting in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 pathway. In humans, SNP309 is shown to associate with accelerated tumor formation in both hereditary and sporadic cancers. A model is proposed whereby SNP309 serves as a rate-limiting event in carcinogenesis.

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    • "With a major rate of fertilization and implantation, the risk of pregnancy loss from other causes also increases. Moreover, even without full understanding of the effect of the p63 polymorphism on its functioning, it is known that the TT genotype of MDM2 (rs2279744) results in lower levels of the protein [20] and Table 2 TP63, TP73 and MDM2 SNPs: allelic and genotypic frequencies in women with RPL and in the control group. "
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    ABSTRACT: Objective: Recent studies have investigated the role of the p53 gene family in reproductive processes. Each member of the gene family acts through different mechanisms: p53 is involved in genomic stability and regulation of blastocyst implantation; p63 acts as a regulator of the quality and maturation of oocytes; and p73 controls the meiotic spindle. Polymorphisms in the genes of the p53 family have been associated with female infertility. One polymorphism in MDM2, the main regulator of the p53 family, has also been associated with this condition. Although polymorphisms in the TP53 gene have been related to recurrent pregnancy loss (RPL), there have been no studies associating polymorphisms in p63 and p73 with RPL. Therefore, the aim of this study was to evaluate the role of polymorphisms in the TP63 (rs17506395), TP73 (rs2273953, rs1801173), and MDM2 (SNP309, rs2279744) genes as risk factors for RPL. Study design: A case-control study was conducted in 153 women with RPL and 143 fertile women with at least two living children and no history of pregnancy loss. Molecular analysis was performed by TaqMan Allelic Discrimination assay. The statistical analysis was performed using SPSS software version 20.0 and the chi-square test, Student's t-test, Mann-Whitney test and logistic regression to compare the evaluated characteristics between both groups and RPL outcome. Results: The allelic and genotypic frequencies did not differ between the groups when analyzed separately, however, the interaction between the TP63 TT and MDM2 TT genotypes was shown to increase the risk of RPL (OR=2.19, CI 95%: 1.28-3.75, p=0.004), even when adjusted for alcohol consumption, smoking, number of pregnancies and ethnicity (OR=1.97, CI 95%: 1.27-3.58, p=0.025). Conclusions: Our results suggest that genes from the p53 family proteins, evaluated here, have an influence on the risk of RPL.
    European Journal of Obstetrics & Gynecology and Reproductive Biology 08/2014; 182C:7-10. DOI:10.1016/j.ejogrb.2014.07.044 · 1.70 Impact Factor
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    • "Loss of p53 function, typically arising through point mutations is seen in 50% of all cancers [3], [4]. In malignancies with wild type p53 status, the activity of p53 is commonly attenuated through overexpression of Mdm2, a key negative regulator [5], [6]. Mdm2 both inhibits the transactivation function of p53 and selectively ubiquitinates p53, targeting it for proteosomal degradation [7]–[10]. "
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    ABSTRACT: As key negative regulator of the p53 tumour suppressor, Mdm2 is an attractive therapeutic target. Small molecules such as Nutlin have been developed to antagonise Mdm2, resulting in p53-dependent death of tumour cells. We have recently described a mutation in Mdm2 (M62A), which precludes binding of Nutlin, but not p53. This Nutlin-resistant variant is not, however, refractory to binding and inhibition by stapled peptide antagonists targeting the same region of Mdm2. A detailed understanding of how stapled peptides are recalcitrant to Mdm2 mutations conferring Nutlin-resistance will aid in the further development of potent Mdm2 antagonists. Here, we report the 2.00 Å crystal structure of a stapled peptide antagonist bound to Nutlin resistant Mdm2. The stapled peptide relies on an extended network of interactions along the hydrophobic binding cleft of Mdm2 for high affinity binding. Additionally, as seen in other stapled peptide structures, the hydrocarbon staple itself contributes to binding through favourable interactions with Mdm2. The structure highlights the intrinsic plasticity present in both Mdm2 and the hydrocarbon staple moiety, and can be used to guide future iterations of both small molecules and stapled peptides for improved antagonists of Mdm2.
    PLoS ONE 08/2014; 9(8):e104914. DOI:10.1371/journal.pone.0104914 · 3.23 Impact Factor
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    • "When T is replaced with G, this increases the affinity of the Sp1 transcription factor and it has been shown that cells carrying the T309G genotype have a 2-3-fold increase in MDM2 mRNA and protein synthesis. This leads to the abrogation of p53 tumor suppressor activity and the development of cancer [23]. "
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    ABSTRACT: Background The MDM2 gene is the major negative regulator of p53, a tumor suppressor protein. Single nucleotide polymorphism in promoter region of MDM2 gene leads to increased expression resulting in higher levels of MDM2 protein. This event increases the attenuation of the p53 pathway. Polymorphisms in this gene can interfere in the regulation of cellular proliferation. We evaluated whether MDM2 SNP309 (rs2278744) associated or not with the use of oral contraceptive can heighten susceptibility to development of cervical lesions in women HPV infected. Methods MDM2 SNP309 (rs2278744) was genotyped in a total of 287 patients using the PCR-RFLP technique. The results were analyzed by UNPHASED v.3.121 and SNPStats programs. Results The three groups (SIL, LSIL and HSIL) showed no significant differences in either genotype or allelic frequencies for MDM2 polymorphisms, except when HSIL was compared with LSIL (p = 0.037; OR = 1.81). Furthermore, in the analysis of contraceptives, a significant association was found between the use of contraceptives and the MDM2 variant in the development of high-grade cervical lesions for the TG genotype (p = 0.019; OR = 2.21) when HSIL was compared with control. When HSIL was compared with LSIL (p = 0.006; OR = 2.27). Conclusion The results of this study suggest that MDM2 SNP309 might be a good marker for assessing the progression of LSIL to HSIL. In addition, they also show that oral contraceptives alone, did not have any effect on the progression or development of cervical lesions. However, they may act synergistically with MDM2 SNP309 (rs2278744) and HPV infection in the development of cervical lesions.
    Infectious Agents and Cancer 07/2014; 9(1):24. DOI:10.1186/1750-9378-9-24 · 2.36 Impact Factor
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