Eugene W. Gerner
Professor, Cell Biology & Anatomy, and Molecular Biophysics;
Director, Specialized Program of Research Excellence (SPORE) in GI Cancer
e-mail: egerner@azcc.arizona.edu
Arizona Cancer Center
1515 N. Campbell Ave.
P.O. Box 245024
Tucson AZ 85724
Phone: 520/626-2197
Fax: 520/626-4480
Summary of Research Activities
Our laboratory investigates the role of genetic and intestinal luminal risk factors in gastrointestinal (GI) carcinogenesis. We have special interests in the roles of the adenomatous polyposis coli (APC) tumor suppressor gene, which is mutated in most sporadic colonic neoplasia, and the K-ras oncogene, which is mutated in a large fraction of colonic and pancreatic neoplasia. We are working to define the normal functions of specific genes in signaling pathways, influenced by APC, leading to cell birth (mitosis) or cell death (apoptosis), and to understand how these functions are altered by mutations. Recent work from our lab has shown that genes involved in arachidonic and amino acid metabolism are downstream effectors of APC and K-ras. We are studying the regulation of enzymes and proteins involved in these metabolic pathways, which produce polyamines and prostaglandins. The polyamines are ubiquitous polycations, and are essential for optimal growth of cells. Inhibiting polyamine and/or prostaglandin synthesis can block epithelial carcinogenesis in experimental animals. Likewise, genetic or pharmacological suppression of cyclooxygenases-1 or -2 (COX-1, COX-2), which produce prostaglandins from arachidonic acid, suppress especially intestinal carcinogenesis. We have found that polyamines and prostaglandins influence cell behaviors, in part, by modulating specific gene expression. Polyamines affect transcription by modifying DNA-protein complex formation, RNA processing via a specific modification of a protein (eIF-5A) involved in RNA transport and degradation, and translation of at least one protein (antizyme) by a novel translational frameshifting mechanism. Prostaglandins influence specific gene expression via their action as ligands for certain transcription factors (PPARs). Lab members are investigating mechanisms of polyamine- and prostaglandin-dependent expression genes in cell and animal models, using cDNA microarray techniques to study global patterns of gene expression and more conventional methodologies to study changes in single genes. We are using this information to develop novel strategies of GI cancer prevention and treatment. We are currently collaborating with physicians at the Arizona Cancer Center and elsewhere to determine whether these strategies can be effectively employed in selected human populations. One current clinical trial involves the treatment of otherwise healthy individuals with precancerous colon polyps, using inhibitors of polyamine synthesis and non-steroidal
anti-inflammatory drugs (NSAIDs).
Selected Publications
Meyskens FL, Jr and Gerner EW (1999) Development of difluoromethylornithine (DFMO) as a chemopreventive agent. Clinical Cancer Research 5, 945-951
Fultz KE and Gerner EW (2002) APC-dependent regulation of ornithine decarboxylase in human colon tumor cells. Molecular Carcinogenes. 34, 10-18
Lawson KR, Marek S, Linehan JA, Woster P, Casero RA Jr, Payne CM and Gerner EW (2002) Toxicity of the polyamine analog CHENSpm is modulated by the FAD-dependent polyamine oxidase. Clinical Cancer Research 8, 1241-1247
Quinones H, List A and Gerner EW (2002) Selective exclusion by the polyamine transporter as a mechanism for the differential radioprotection of amifostine derivatives. Clinical Cancer Research 8, 1295-1300
Baines A, Taylor-Parker M, Goulet A-C, Renaud C, Gerner EW and Nelson M (2002) Selenomethionine inhibits growth and suppresses cyclooxygenase-2 (COX-2) protein expression in human colon cancer cell lines. Cancer Biology & Therapy 1, 370-374
Taylor Parker, M and Gerner EW (2002) Polyamine-dependent posttranscriptional regulation of COX-2. Biochimie 84, 815-819
Collaborative Research
Jesse D. Martinez, Ph.D. Radiation Oncology
Harris Bernstein, Ph.D. Microbiology & Immunology
Claire Payne, Ph.D. Microbiology & Immunology
David Besselsen, DVM, Ph.D. University Animal Care
Denise Roe, Dr. P.H. Family & Community Medicine
David Alberts, M.D. Medicine
Evan M. Hersh, M.D. Medicine
Kathy McGovern, Ph.D. Radiation Oncology
David O’Brien, Ph.D. Chemistry
Mark Nelson, Ph.D. Pathology 8.
