Abstract
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.
MeSH terms
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Adult
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Age of Onset
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Animals
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Base Sequence / genetics
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Cell Line
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Drosophila
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Female
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Gene Frequency / genetics
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Genetic Predisposition to Disease / genetics*
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Genetic Testing
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Humans
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Male
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Molecular Sequence Data
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Mutation / genetics
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Neoplasms / genetics*
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Neoplasms / metabolism
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Nucleotides / genetics
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Polymorphism, Single Nucleotide*
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-mdm2
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RNA, Messenger / metabolism
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Sp1 Transcription Factor / genetics
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Transcriptional Activation / genetics
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Tumor Suppressor Protein p53 / genetics*
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Tumor Suppressor Protein p53 / metabolism
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Up-Regulation / genetics
Substances
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Nuclear Proteins
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Nucleotides
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Proto-Oncogene Proteins
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RNA, Messenger
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Sp1 Transcription Factor
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2