Dan A. Dixon, PhD

Associate Professor
Co-Leader, Cancer Prevention Program, University of Kansas Cancer Center
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 cancer (CRC) is a leading cause of cancer incidence and death among adult Americans. Commonly observed in colon cancer cells and tumors is overexpression of many oncogenic and inflammation-associated genes. These factors allow the tumor cell to proliferate, promote angiogenesis, escape apoptosis, and metastasize. In normal cells, post-transcriptional mechanisms involving RNA-binding proteins and microRNAs target oncogenic mRNAs for rapid degradation. However, this critical mechanism is commonly lost in tumor cells allowing for oncogenic gene overexpression. By better understanding these post-transcriptional mechanisms, our goal is to identify new molecular targets for controlling oncogenic gene expression that can improve on CRC prevention and treatment.

Role of RNA-Binding Proteins in Cancer
A critical point in controlling oncogenic gene expression in normal cells occurs through 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. A common feature observed in many tumor types is the overexpression of the stability factor HuR and loss of the decay factor TTP. These combined defects in tumor cells allow oncogenic mRNA to escape their normal fate being degraded. Current projects involve understanding how these RNA-binding proteins act as an oncogene and tumor suppressor. By their ability to control a large number of mRNA 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 side effects of these drugs have limited their use for chemoprevention. 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

Shufei Zhuang, PhD Laboratory Manager	Fernando Blanco, PhD Postdoctoral Fellow	Cyril Sobolewski, PhD Postdoctoral Fellow

Liangyan Hu, PhD Research Associate	Yuan Li IGPBS Rotation Student

Selected Publications

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. View PubMed 

2.    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. View PubMed

3.    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. View PubMed

4.    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. View PubMed

5.    Dixon, D.A. (2004) Dysregulated Post-Transcriptional Control of COX-2 Gene Expression in Cancer. Curr. Pharm. Des. 10:635-646. View PubMed

6.    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. View PubMed

7.    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. View PubMed

8.    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. View PubMed

9.    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. View PubMed

10.  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. View PubMed

11.  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. View PubMed

12.  Sanduja, S. and Dixon, D.A. (2010) Tristetraprolin and E6-AP: Killing the Messenger in Cervical Cancer. Cell Cycle, 9:3135-3136. View PubMed

13.  Moore, A.E., Young, L.E. and Dixon, D.A. (2011) MicroRNA and AU-Rich Element Regulation of Prostaglandin Synthesis. Cancer and Metastasis Reviews, 30:419-435. View PubMed

14.  Young, L.E., Moore, A.E., Sokol, L., Meisner-Kober, N. and Dixon, D.A. (2012) The mRNA Stability Factor HuR Inhibits MicroRNA-16 Targeting of Cyclooxygenase-2. Mol. Cancer Res. 10:167-180. View PubMed

15.  Moore, A.E., Young, L.E. and Dixon, D.A. (2012) A Common Single-Nucleotide Polymorphism in Cyclooxygenase-2 Disrupts MicroRNA-Mediated Regulation. Oncogene, 31:1592-1598. View PubMed

16.  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. View PubMed

17.  Dovizio, M., Tacconelli, S., Ricciotti, E., Bruno, A., Anzellotti, P., Francesco, L.D., Sala, P., Signorini, S., Bertario, L., Dixon, D.A., Lawson, J., Steinhiber, D., FitzGerald, G.A., and Patrignani, P. (2012) Effects of Celecoxib on Systemic Prostanoid Biosynthesis and Circulating Angiogenesis Proteins in Familiar Adenomatous Polyposis Patients. J. Pharmacol. Exp. Ther. 341:242-250. View PubMed

18.  Rounbehler, R.J., Fallahi, M., Yang, C., Steeves, M.A., Li, W., Doherty, J.R., Schaub, F.X., Sanduja, S., Dixon, D.A., Blackshear, P.J. and Cleveland, J.L. (2012) Tristetraprolin is a Tumor Suppressor that Impairs Myc-Induced Lymphoma and Abolishes the Malignant State. Cell, 150:563-574. View PubMed

19.  Dixon, D.A., Blanco, F.F., Bruno, A. and Patrignani, P. (2013) Mechanistic Aspects of COX-2 Expression in Colorectal Neoplasia. Recent Results Cancer Res. 191:7-37. View PubMed

20. Upadhyay, R., Sanduja, S., Kaza, V. and Dixon, D.A. (2013) Genetic Polymorphisms in RNA Binding Proteins Contribute to Breast Cancer Survival. Int. J. Cancer, 132:E128-E138. View PubMed