Contrasting Effects Of An Mdm2 Functional Polymorphism On Tumor Phenotypes

Author

Guadalupe J. Ortiz IV, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical SciencesFollow

Author ORCID Identifier

0000-0002-8728-5090

Date of Graduation

8-2017

Document Type

Dissertation (PhD)

Program Affiliation

Genes and Development

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Guillermina Lozano, Ph.D.

Committee Member

David D. Johnson, Ph.D.

Committee Member

Xiaobing Shi, Ph.D.

Committee Member

Sean M. Post, Ph.D.

Committee Member

Pierre McCrea, Ph.D.

Abstract

Cancer predisposition by the cooperation of genetic variants, such as single nucleotide polymorphisms (SNPs), may be of much greater significance to public health than previously appreciated. Functional polymorphisms are genetic variants that alter gene function. Meta-analyses associate many functional polymorphisms with cancer risk. The MDM2 SNP309G allele is a cancer-associated functional polymorphism positioned in the MDM2 P2 promoter that enhances transcription factor SP1 binding, resulting in elevated levels of MDM2 concomitant with decreased p53 tumor-suppressor activity. Mdm2^SNP309G/G mice are more prone to spontaneous tumor formation than Mdm2^SNP309T/T mice, providing direct evidence for the impact of this SNP on tumor development. We examined the impact of SNP309 on cancer risk in response to environmental factors by treating SNP309 mice with ionizing radiation, UVB, or Benzo(a)pyrene. The results show that SNP309G cooperates with ionizing radiation to exacerbate tumor development. Contrastingly, ultraviolet B light or Benzo(a)pyrene exposure of skin indicates that SNP309G allele protects against squamous cell carcinoma susceptibility. These contradicting differences led us to interrogate the mechanism by which Mdm2 SNP309 regulates tumor susceptibility in a tissue-specific manner. The assessment of potential transcriptional regulators in ENCODE ChIP-seq database identified transcriptional repressor E2F6 as a possible negative regulator of MDM2 expression. Our data show that E2F6 protein is expressed at higher levels in skin keratinocytes of SNP309 mice as compared to lymphatic tissues. Furthermore, E2F6 binds and suppresses Mdm2 expression in cells harboring the SNP309G allele but not the SNP309T allele. Thus, the Mdm2 SNP309G allele exhibits tissue-specific regulation and differentially impacts cancer risk.

Keywords

Mdm2, SNP309, IR, B(a)P, UVB, p53, E2F6