Impact of the Mdm2(SNP309-G) allele on a murine model of colorectal cancer.

Abstract

A single-nucleotide polymorphism (SNP) in the promoter of the Mdm2 gene (Mdm2(SNP309-G)) results in an increased Mdm2 expression, partial attenuation of the p53 pathway and accelerated tumor development. Clinical case-control studies indicate the Mdm2(SNP309-)(G) allele associates with a significant increase in colorectal cancer (CRC) risk that is heightened in women, but the biological significance of this polymorphism has never been directly evaluated. To examine whether the Mdm2(SNP309-)(G) allele contributes to colorectal cancer, we generated cohorts of mice harboring either the G (minor allelic variant) or T (major allelic variant) allele and treated them with azoxymethane (AOM), a carcinogen that induces sporadic colorectal cancer. Mdm2(SNP309-G/G) mice displayed a significant reduction in survival following AOM treatment with more colonic lesions in a wider distribution throughout the lower and upper colon and an attenuated apoptotic response following exposure. AOM did not significantly induce stabilization of wild-type p53 or activate p53 downstream targets following AOM treatment, regardless of the genotype. Instead, Mdm2(SNP309-G/G) colons had significant changes in the expression of genes that regulate Mdm2 transcription (ERα and Sp1) as well as downstream targets of Mdm2. Together these results suggest the Mdm2(SNP309-)(G) allele significantly impacts CRC through mechanisms outside the p53 pathway.

• Authors: X Zhang, L Pageon, S M Post
• Journal: Oncogene (Oncogene) Vol. 34 Issue 33 Pg. 4412-20 (Aug 13 2015) ISSN: 1476-5594 [Electronic] England
• PMID: 25435368 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Suppressor Protein p53
• Mdm2 protein, mouse
• Proto-Oncogene Proteins c-mdm2
• Azoxymethane

Topics

• Alleles
• Animals
• Apoptosis (genetics)
• Azoxymethane (pharmacology)
• Colorectal Neoplasms (chemically induced, genetics)
• Genetic Predisposition to Disease (genetics)
• Genotype
• Mice
• Mice, Inbred C57BL
• Polymorphism, Single Nucleotide (genetics)
• Proto-Oncogene Proteins c-mdm2 (genetics)
• Risk
• Transcription, Genetic (genetics)
• Tumor Suppressor Protein p53 (genetics)