Jesse D. Martinez
Professor of Cell Biology & Anatomy and Radiation Oncology
e-mail: jmartinez@azcc.arizona.edu
Arizona Cancer Center
1515 N. Campbell Ave.
P.O. Box 245024
Tucson AZ 85724
Phone: 520/626-4250
Fax: 520/626-4480
Summary of Research Activities
Mechanisms of Colon Cancer Chemoprevention
Colorectal carcinogenesis is a multistep process that involves a series of genetic mutations that result in transformation of normal colonocytes into neoplastic cells and the development of adenomas that, with time, progress to invasive cancers. This process is influenced by both genetic background and environment, with diet as the chief colonic environmental factor.
A primary focus of my research in this area is elucidation of the mechanism by which the diet-influenced levels of bile acids alter colon tumor etiology. We are approaching this problem by conducting studies at the molecular level in colon tumor cells in culture, in transgenic animal models with specific genetic lesions, and in clinical trials. Through these combined studies we have shown that the bile acid deoxycholic acid stimulates the activity of the AP-1 protooncogene. AP-1 leads to aberrant proliferation and reduced apoptosis via a signaling pathway that is commonly stimulated by growth factors. Moreover, this pathway appears to be activated in naturally occurring tumors, suggesting that deoxycholic acid may act by mimicking the effects of genetic mutations that can lead to colon tumor development.
Mechanisms of p53 function and dysfunction Mutations in the p53 tumor-suppressor gene are the most frequent genetic abnormality associated with human cancers. Fully half of all human tumors have mutations that lead to inactivation of this protein Loss of p53 function fosters tumor development by increasing genetic instability. This also decreases cellular sensitivity to chemotherapy drug-induced apoptosis, making tumors with mutant p53 resistant to conventional cancer therapies.
My work in this area focuses on understanding how the myriad signals that act on p53 integrate to produce a coordinated response to genotoxic agents such as ionizing radiation and chemotherapy drugs. We are using a temperature-sensitive version of p53, combined with a genetic approach, to identify critical regulators of p53 signal transduction in order to tease out the critical signaling components that respond to genotoxic stimuli. The ultimate goal of this research is to utilize the information gained through these studies to develop therapeutic methods that restore or mimic wild-type p53 tumor-suppressor function in tumor cells.
Selected Publications
Martinez JD, Stratagoules ED, Payne CM, Powell A, Powell M, LaRue J, Earnest DL. Different bile acids exert distinct biological effects: induction of apoptosis by deoxycholic acid and growth arrest by ursodeoxycholic acid. Nutrition and Cancer 31(2):111-118, 1998.
Martinez JD, Craven M, Joseloff E, Milczarek G, Bowden GT. Regulation of DNA binding and transactivation in p53 by nuclear localization and phosphorylation. Oncogene 14:2511-2520, 1997.
Martinez JD, Pennington ME, Craven MT, Warters RL, Cress AE. Free radicals generated by ionizing radiation signal nuclear translocation of p53. Cell Growth and Differentiation 8:941-949, 1997.
Collaborative Research
Eugene Gerner, Ph.D., Radiation Oncology, and Marianne Broome-Powell, Ph.D., Medicine: role of protein kinase C in apoptosis in colon cancer.
Anne Cress, Ph.D., Radiation Oncology, and Ray Warters, Ph.D., Radiation Oncology, University of Utah: radiation induced signaling pathway that results in activation of p53.
G. Tim Bowden, Ph.D., Radiation Oncology: regulation of p53 tumor suppressor activity through phosphorylation.
G. Timothy Bowden, Ph.D., Radiation Oncology
Molly Kulesz-Martin, Ph.D., Oregon Health and Science University
Kit Lam, M.D., Ph.D., University of California, Davis
Roger Miesfeld, Ph.D., Biochemistry and Molecular Biophysics
Raymond B. Nagle, M.D., Ph.D., Pathology
J. Thomas Parsons, Ph.D., University of Virginia Health Sciences Center
