Dan A. Dixon, PhD

Associate Professor
Adjunct faculty, Department of Molecular & Integrative Physiology
Ph.D.: Northwestern University
Postdoctoral: University of Utah, Vanderbilt University Medical Center

Post-Transcriptional Gene Regulation in Colorectal Cancer
Colorectal cancers are a leading cause of cancer incidence and death among adult Americans. Commonly observed in colon cancer cells and tumors is overexpression of many growth- and inflammation-associated genes. The overabundance of these factors, which include proto-oncogenes, inflammatory mediators, and angiogenic growth factors, allows the tumor cell to proliferate, promote angiogenesis, escape apoptosis, and metastasize. In normal cells, post-transcriptional mechanisms involving RNA-binding proteins and microRNAs play a critical role by identifying these oncogenic mRNAs and targeting them for rapid decay. Whereas, in tumor cells loss of this critical mechanism is commonly observed allowing for significant oncogenic gene overexpression. By better understanding these post-transcriptional mechanisms, we aim to identify and define new molecular targets for controlling oncogenic gene expression in colorectal cancer and improve on current treatment and prevention strategies.

Role of RNA-Binding Proteins in Cancer
A critical point in controlling the expression of growth- and inflammation-associated genes in normal cells occurs through post-transcriptional mechanisms that regulate mRNA decay. The two primary RNA-binding proteins associated with this are the mRNA stability factor HuR and the mRNA decay factor TTP. Both of these factors bind AU-rich mRNA elements (ARE) present in a majority of cancer-associated mRNAs and target the mRNA for stabilization or rapid decay. However, a common feature observed in various tumor types is the overexpression of the stability factor HuR and loss of expression of the decay factor TTP. These combined defects allow for stabilization and overexpression of cancer-associated growth factors. Current projects involve characterization of the novel tumor promoting function of HuR and tumor suppressing function of TTP. By their ability to control a large number of oncogenic transcripts, we are examining these RNA-binding proteins as therapeutic targets that can counteract the oncogenic effects of mRNA stabilization.

Regulation of COX-2 Expression in Cancer
The inducible prostaglandin synthase COX-2 mediates inflammatory responses and plays a pivotal role in the pathogenesis of several cancer types due to its overexpression. Various studies have demonstrated the chemopreventive effects of COX-2 inhibition using non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, however concerns related to the unwanted side effects of these drugs have limited their use as anti-cancer compounds. Our research has shown that post-transcriptional regulation is an essential mechanism regulating COX-2 gene expression and loss of this regulation occurs in cancer cells. Using molecular, cellular, and in vivo approaches, we are examining the functional significance post-transcriptional regulation plays in controlling COX-2 expression.

Lab Members

Fernando Blanco, PhD Postdoctoral Fellow

Ashleigh Moore Graduate Student

Selected Publications (Bold = trainee)

1. Dixon, D.A., Kaplan, C.D., McIntyre, T.M., Zimmerman, G.A., and Prescott, S.M. (2000) Post-Transcriptional Control of Cyclooxygenase-2 Gene Expression: Role of the AU-Rich 3'Untranslated Region. J. Biol. Chem. 275:11750-11757.
2. Sheng, H., Shao, J., Dixon, D.A., Williams, C.S., Prescott, S.M., DuBois, R.N., and Beauchamp, R.D. (2000) TGF-b1 Enhances Ras-induced Expression of Cyclooxygenase-2 in Intestinal Epithelial Cells via Stabilization of mRNA. J. Biol. Chem. 275:6628-6635.
3. Lindemann, S., Tolley, N.D., Dixon, D.A., McIntyre, T.M., Prescott, S.M., Zimmerman, G.A., and Weyrich, A.S. (2001) Activated Platelets Mediate Inflammatory Signaling by Regulated Interleukin-1b Synthesis. J. Cell. Biol. 154: 485-490.
4. Dixon, D.A., Tolley, N.D., King, P.H., Nabors, L.B., McIntyre, T.M., Zimmerman, G.A., and Prescott, S.M. (2001) Altered Expression of the mRNA Stability Factor HuR Promotes Cyclooxygenase-2 Expression in Colon Cancer Cells. J. Clin. Invest. 108:1657-1665.
5. Dixon, D.A. (2003) Regulation of COX-2 Expression in Human Cancer. Prog. Exp. Tumor Res. 37: 70-89.
6. Sawaoka, H., Dixon, D.A., Oates, J.A., and Boutaud, O. (2003) Tristetrapolin Binds to the 3' Untranslated Region of Cyclooxygenase-2 mRNA: A Polyadenylation Variant in a Cancer Cell Line Lacks the Binding Site. J. Biol. Chem. 278:13929-13935.
7. Dixon, D.A., Balch G.C., Kedersha N., Anderson, P., Zimmerman, G.A., Beauchamp, R.D., and Prescott, S.M. (2003) Regulation of Cyclooxygenase-2 Expression by the Translational Silencer TIA-1. J. Exp. Med. 198: 475-481.
8. Subbaramaiah, K., Marmo, T.P., Dixon, D.A., and Dannenberg, A.J. (2003) Regulation of Cyclooxygenase-2 mRNA stability by Taxanes. Evidence for Involvement of p38, MAPKAP-K2 and HuR. J. Biol. Chem. 278: 37637-37647.
9. Dixon, D.A. (2004) Dysregulated Post-Transcriptional Control of COX-2 Gene Expression in Cancer. Curr. Pharm. Des. 10:635-646.
10. Peng, G., Dixon, D.A., Muga, S., Smith, T.J., Wargovich, M.J. (2006) Green Tea Polyphenol (-) Epigallocatechin-3-gallate Inhibits Cyclooxygenase-2 Expression in Colon Carcinogenesis. Mol. Carcinog. 45:309-319.
11. Peng G., Wargovich M.J. and Dixon, D.A. (2006) Anti-Proliferative Effects of Green Tea Polyphenol EGCG on Ha-ras-induced Transformation of Intestinal Epithelial Cells. Cancer Lett. 238:260-270.
12. Shiou, S.-R., Datta, P.K., Dhawan, P.,  Law, B.K., Yingling, J.M., Dixon, D.A., Beauchamp, R.D. (2006) Smad4-dependent Regulation of uPA Secretion and RNA Stability Associated with Invasiveness by Autocrine and Paracrine TGF-beta. J. Biol. Chem. 281:33971-33981.
13. Dixon, D.A., Tolley, N.D., Bemis-Standoli, K., Martinez, M.L., Weyrich, A.S, Morrow, J.D., Prescott, S.M., Zimmerman, G.A. (2006) Expression of COX-2 in Platelet-Monocyte Interactions Occurs via Combinatorial Regulation Involving Adhesion and Cytokine Signaling. J. Clin. Invest. 116: 2727-2738.
14. Gong, Z., Hebert, J.R., Bostick, R.M., Deng, Z., Hurley, T.G., Dixon, D.A., Nitcheva, D., and Xie, D. (2007) Common Polymorphisms in 5- and 12- Lipoxygenase Genes and Risk of Incident, Sporadic Colorectal Adenoma. Cancer, 109: 2727-2738.
15. Kanies, C.L., Smith, J.J., Kis, C., Schmidt, C., Levy, S., Khabar, K.S.A., Morrow, J., Deane, N., Dixon, D.A., Beauchamp, R.D. (2008) Oncogenic Ras and TGF-b Synergistically Regulate AU-rich Element-Containing mRNAs during Epithelial-Mesenchymal Transition. Mol. Cancer Res. 6:1124-1136.
16. Gong, Z., Bostick, R.M., Xie, D., Hurley, T.G., Deng, Z., Dixon, D.A., Zhang, J., and Hebert, J.R. (2009) Genetic polymorphisms in the cyclooxygenase-1 and cyclooxygenase-2 genes and risk of colorectal adenoma. Int. J. Colorectal Dis. 24:647-654.
17. Young, L.E., Sanduja, S., Bemis-Standoli, K., Pena, E.A., Price, R.L., Dixon, D.A. (2009) The mRNA Binding Proteins HuR and Tristetraprolin Regulate Cyclooxygenase 2 Expression During Colon Carcinogenesis. Gastroenterology 136:1669-1679.
18. Sanduja, S., Kaza, V., Dixon, D.A. (2009) The mRNA Decay Factor Tristetraprolin (TTP) Induces Senescence in Human Papillomavirus-Transformed Cervical Cancer Cells by Targeting E6-AP Ubiquitin Ligase. Aging, 1:803-817.
19. Young, L.E. and Dixon, D.A. (2010) Post-Transcriptional Regulation of Cyclooxygenase-2 Expression in Colorectal Cancer. Curr. Colorectal Cancer Rep. 6:60-67.
20. Sanduja, S., Blanco, F.F., Dixon, D.A. (2010) The Roles of TTP and BRF Proteins in Regulated mRNA Decay. Wiley Interdisciplinary Reviews: RNA 2:42-57.
21. Sanduja, S. and Dixon, D.A. (2010) Tristetraprolin and E6-AP: Killing the Messenger in Cervical Cancer. Cell Cycle, 9:3135-3136.
22. Moore, A.E., Young, L.E. and Dixon, D.A. (2011) A Common Single-Nucleotide Polymorphism in Cyclooxygenase-2 Disrupts MicroRNA-Mediated Regulation. Oncogene, in press.
23. Moore, A.E., Young, L.E. and Dixon, D.A. (2011) MicroRNA and AU-Rich Element Regulation of Prostaglandin Synthesis. Cancer and Metastasis Reviews, in press.
24. Dixon, D.A., Blanco, F.F., Bruno, A. and Patrignani, P. (2011) Mechanistic Aspects of COX-2 Expression in Colorectal Neoplasia. Prospects for Chemoprevention of Colorectal Neoplasia - Emerging Role of Anti Inflammatory Drugs. eds. Detering, E. and Chan, A., Springer-Verlag, in press.
25. Young, L.E., Moore, A.E., Sokol, L., Meisner-Kober, N. and Dixon, D.A. (2011) The mRNA Stability Factor HuR Inhibits MicroRNA-16 Targeting of Cyclooxygenase-2. Mol. Cancer Res. in press.
26. Sanduja, S., Blanco, F.F., Young, L.E., Kaza, V., and Dixon, D.A. (2012) The Role of Tristetraprolin in Cancer and Inflammation. Frontiers in Bioscience, 17:174-188.