A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development.
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.
Post
Sean M
SM
Department of Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Quintás-Cardama
Alfonso
A
Pant
Vinod
V
Iwakuma
Tomoo
T
Hamir
Amir
A
Jackson
James G
JG
Maccio
Daniela R
DR
Bond
Gareth L
GL
Johnson
David G
DG
Levine
Arnold J
AJ
Lozano
Guillermina
G
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
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