title: A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development.
abstract: MDM2, a negative regulator of p53, is elevated in many cancers that retain wild-type p53. A single nucleotide polymorphism (SNP) in the human MDM2 promoter increases the affinity of Sp1 resulting in elevated MDM2 levels. We generated mice carrying either the MDM2(SNP309T) or the MDM2(SNP309G) allele to address the impact of MDM2(SNP309G) on tumorigenesis. Mdm2(SNP309G/G) cells exhibit elevated Mdm2 levels, reduced p53 levels, and decreased apoptosis. Importantly, some Mdm2(SNP309G/G) mice succumbed to tumors before 1 year of age, suggesting that this allele increases tumor risk. Additionally, the Mdm2(SNP309G) allele potentiates the tumor phenotype and alters tumor spectrum in mice inheriting a p53 hot-spot mutation. These data provide causal evidence for increased cancer risk in carriers of the Mdm2(SNP309G) allele.
authors.affiliation: Department of Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Post
authors.forename: Alfonso
authors.initials: A
authors.lastname: Quintás-Cardama
authors.forename: Vinod
authors.initials: V
authors.lastname: Pant
authors.forename: Tomoo
authors.initials: T
authors.lastname: Iwakuma
authors.forename: Amir
authors.initials: A
authors.lastname: Hamir
authors.forename: James G
authors.initials: JG
authors.lastname: Jackson
authors.forename: Daniela R
authors.initials: DR
authors.lastname: Maccio
authors.forename: Gareth L
authors.initials: GL
authors.lastname: Bond
authors.forename: David G
authors.initials: DG
authors.lastname: Johnson
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D008926:Plicamycin / Q000031:analogs & derivatives / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D016159:Tumor Suppressor Protein p53; C066851:mithramycin A; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D008926:Plicamycin