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

Bond, Gareth L.; Hu, Wenwei; Bond, Elisabeth E.; Robins, Harlan; Lutzker, Stuart; Arva, Nicoleta C.; Bargonetti, Jill; Bartel, Frank; Täubert, Helge; Wuerl, Peter; Onel, Kenan; Yip, Linwah; Hwang, Shih Jen; Strong, Louise C.; Lozano, Guillermina; Levine, Arnold J.

doi:10.1016/j.cell.2004.11.022

Cited by 1,127 publications

(1,419 citation statements)

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“…2,18 Two features of the p53 72Pro allele can be hypothesized to contribute to this outcome, that is, its increased transcriptional activity on target genes and the weaker interaction with the MDM2 protein, the first by enhancing MDM2 hyperexpression, and the second by downregulating the mitochondrial control of the apoptotic pathway. 7 On the other hand, our finding of a weak negative association of the MDM2 G allele is in contrast with reports of its preferential transmission to RB patients, 13 modifier role in Li-Fraumeni syndrome 9,19 and association with common cancers. 20 Nevertheless, our findings seem plausible, considering that the association only holds in p53-mutated cancers.…”

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“…7 The G allele of MDM2 309SNP (c.14+309T4G, rs2279744:T4G), adjacent to p53-responsive elements of the inducible intronic P2 promoter, activates MDM2 transcription 8 and results in overdegradation of p53. 9 Several studies have highlighted the risk-modifying effect of these polymorphisms in common cancers and the rare Li-Fraumeni syndrome caused by germinal TP53 mutations. [10][11][12] The possible role of the MDM2 309SNP in RB has only recently been addressed through a family-based approach.…”

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p53 Arg72Pro and MDM2 309 SNPs in hereditary retinoblastoma

et al. 2011

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The tumor suppressor p53 and its negative regulator MDM2 have crucial roles in a variety of cellular functions such as the control of the cell cycle, senescence, genome stability and apoptosis, and are frequently deregulated in carcinogenesis. Previous studies have highlighted the contribution of the common functional polymorphisms p53 p.Arg72Pro and MDM2 309SNP to the risk of both common cancers and Li-Fraumeni syndrome. Their possible role in retinoblastoma has recently been addressed by Casté ra et al, who however only studied the MDM2 309SNP. Here, for the first time, we analyzed both single nucleotide polymorphisms (SNPs) in a case-control study of 111 Italian hereditary retinoblastoma patients. We found a significant association of the p53 Pro/Pro genotype with the disease (odds ratio¼3.58, P¼0.002). The MDM2 309SNP showed a weak negative association of allele G that deserves further investigation. These findings further support the hypothesis that genetic variability of the p53 pathway contributes to the individual susceptibility to retinoblastoma, as shown for Li-Fraumeni syndrome and a variety of non-hereditary cancers. Keywords: hereditary retinoblastoma; MDM2; p53; single nucleotide polymorphisms Retinoblastoma (RB, OMIM#180200), the most common primary intraocular malignancy in children, affecting 1:14 000-1:22 000 live births, is caused by biallelic inactivation of RB1. 1 In about 40% of patients a germline mutation inactivates one allele and a somatic one the second allele (hereditary RB), whereas in non-hereditary RB, both alleles are inactivated somatically. Although most children with hereditary RB show multiple bilateral tumors, a significant proportion of carriers remain unaffected or only develop unilateral tumors, or benign retinomas. 2 Penetrance and expressivity of hereditary RB may depend on the type of inherited mutation, and can vary even within families and among patients with identical mutations. [3][4][5] This indicates a role of modifiers that may affect genome stability to favor the occurrence of somatic mutations, and/or the apoptotic pathway to induce loss or maintenance of the mutated retinoblasts.The p53 pathway, the master control system of these processes, is controlled by a feedback autoregulatory loop in which p53 transcriptionally activates MDM2, that in turn functions as a negative regulator by promoting the proteolytic degradation of p53. Interestingly, this circuit can also target pRB to degradation and in physiological condition controls the cell cycle and apoptosis of the retinal cone precursors, from which the RB cell lineage originates. 6 In RB, p53 is not usually mutated nor is MDM2 amplified. Rather, the expression of MDM2 is highly induced and represses p53, 6 thus leaving ample space for constitutional polymorphism of p53 and/or MDM2 to affect the fate of the RB lineage.The 72Pro allele of p53 single nucleotide polymorphisms (SNP) (p.Arg72Pro, rs1042522:G4C) features a reduced proapototic activity compared with the 72Arg allele, and together with its more effici...

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p53 Arg72Pro and MDM2 309 SNPs in hereditary retinoblastoma

et al. 2011

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“…11,38 The presence of SNP309G in the promoter may increase MDM2 expression. 39 However, no overall enrichment of SNP309G was observed in this tumor material compared with that from healthy Norwegians, arguing against any predisposing effect, 21 and no clear association between MDM2 expression level and SNP309 was found in this panel. The latter point is perhaps not surprising, because MDM2 expression is highly associated with gain or gene amplification, and there was no tendency for specific alleles to be overrepresented in tumors with altered MDM2 copy number.…”

Section: Discussionmentioning

confidence: 59%

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

Ohnstad¹,

Castro²,

Sun³

et al. 2012

Cancer

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BACKGROUND: Relatively few sarcomas harbor TP53 (tumor protein p53) mutations, but in many cases, amplification of MDM2 (murine double minute 2) effectively inactivate p53. The p53 pathway activity can also be affected by normal genetic variation. METHODS: The mutation status of TP53 and expression of MDM2, TP53, and their genetic variants SNP309 and R72P (Arg72Pro) were investigated in 125 sarcoma patient samples and 18 sarcoma cell lines. Association of the different genotypes and gene aberrations with chemotherapy response and survival, as well as response to MDM2 antagonists in vitro was evaluated. RESULTS: Twenty-two percent of the tumors had mutant TP53 and 20% MDM2 gene amplification. Patients with wild-type TP53 (TP53 Wt ) tumors had improved survival (P < .001) and TP53 Wt was an independent prognostic factor (hazard ratio ¼ 0.41; 95% confidence interval ¼ 0.23-0.74; P ¼ .03). Interestingly, there was a trend toward longer time to progression after chemotherapy for tumors with the apoptosis-prone p53 variant R72 (P ¼ .07), which was strongest with doxorubicin/ifosfamide-based regimens (P ¼ .01). Liposarcomas had low R72 frequency (33% versus 56%), but increased levels of MDM2 and MDM4 (51% and 11%, P < .001). MDM2 overexpression on a TP53 Wt background predicted better response to MDM2 antagonist Nutlin-3a, irrespective of R72P or SNP309 status. CONCLUSIONS: Improved survival after chemotherapy was found in patients with TP53 Wt tumors harboring the R72 variant. MDM2 overexpression in TP53 Wt tumors predicted good response to MDM2 antagonists, irrespective of R72P or SNP309 status. Thus, detailed TP53 and MDM2 genotype analyses prior to

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“…One polymorphism in the promoter region of MDM2, T309G (rs2279744), has been reported and cells carrying the GG genotype show high-level expression of MDM2 protein and significant attenuation of the P53 pathway. 6 This polymorphism is supposed to be associated with early onset of breast cancer in Li-Fraumeni patients and with risk for gastric carcinoma. 7,8 The Arg72 variant of P53 Arg72Pro (rs1042522) induces apoptosis more effectively than the Pro72 variant.…”

Section: Introductionmentioning

confidence: 99%

Association of genetic polymorphisms in MDM2, PTEN and P53 with risk of esophageal squamous cell carcinoma

Zhang

Ning

et al. 2012

J Hum Genet

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Genetic variations in MDM2, PTEN and P53 might be involved in cancer susceptibility. To assess the contribution of polymorphisms in these three genes to the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese population, we genotyped MDM2 T309G, Del1518, PTEN rs701848, rs2735343 and P53 Arg72Pro polymorphisms using PCR-restriction fragment length polymorphism analysis in 226 ESCC cases and 226 cancer-free controls. Here we showed that the risk of ESCC was elevated in subjects with any of the variant genotypes of PTEN rs2735343 and P53 Arg72Pro polymorphisms, but not any genotype of MDM2 or PTEN rs701848. Moreover, multiplicative interactions were observed between PTEN rs2735343 and P53 Arg72Pro or smoking status on risk of ESCC. Our study firstly indicated that PTEN rs2735343 might be a susceptibility factor for ESCC and reaffirmed the role of P53 Arg72Pro in ESCC in this Chinese population, but did not replicate the positive association between MDM2 T309G and ESCC found previously.

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

Cited by 1,127 publications

References 23 publications

p53 Arg72Pro and MDM2 309 SNPs in hereditary retinoblastoma

p53 Arg72Pro and MDM2 309 SNPs in hereditary retinoblastoma

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

Association of genetic polymorphisms in MDM2, PTEN and P53 with risk of esophageal squamous cell carcinoma

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