Contrasting Effects of An Mdm2 Functional Polymorphism On Tumor Phenotypes

<p>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 <em>MDM2 SNP309G</em> allele is a cancer-associated functional polymorphism positioned in the <em>MDM2</em> P2 promoter that enhances transcription factor SP1 binding, resulting in elevated levels of MDM2 concomitant with decreased p53 tumor-suppressor activity. <em>Mdm2^SNP309G/G</em> mice are more prone to spontaneous tumor formation than <em>Mdm2^SNP309T/T</em> mice, providing direct evidence for the impact of this SNP on tumor development. We examined the impact of <em>SNP309</em> on cancer risk in response to environmental factors by treating <em>SNP309</em> mice with ionizing radiation, UVB, or Benzo(a)pyrene. The results show that <em>SNP309G</em> cooperates with ionizing radiation to exacerbate tumor development. Contrastingly, ultraviolet B light or Benzo(a)pyrene exposure of skin indicates that <em>SNP309G</em> allele <em>protects</em> against squamous cell carcinoma susceptibility. These contradicting differences led us to interrogate the mechanism by which <em>Mdm2 SNP309</em> 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 <em>MDM2</em> expression. Our data show that E2F6 protein is expressed at higher levels in skin keratinocytes of <em>SNP309</em> mice as compared to lymphatic tissues. Furthermore, E2F6 binds and suppresses <em>Mdm2</em> expression in cells harboring the <em>SNP309G</em> allele but not the <em>SNP309T</em> allele. Thus, the <em>Mdm2</em> <em>SNP309G</em> allele exhibits tissue-specific regulation and differentially impacts cancer risk.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2017

Authors dc:creator

• Ortiz, Guadalupe J, IV
• <p>0000-0002-8728-5090</p>

Contributors dc:contributor

• Guillermina Lozano, Ph.D.
• David D. Johnson, Ph.D.
• Xiaobing Shi, Ph.D.

• Mdm2
• SNP309
• IR
• B(a)P
• UVB
• p53
• E2F6
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/804

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1850