George Timothy "Tim"  Bowden, Ph.D.

Professor, Radiation Oncology, Cell Biology & Anatomy, Pharmacology & Toxicology

Chair, Cancer Biology Graduate Interdisciplinary Program, Department of Cell Biology and Anatomy

Leon Levy- Cancer Center 4999c,
P. O. Box: 245024,
Tucson AZ 85724-5024
Phone: 626-6006; 626-6747
E-mail: bowden@azcc.arizona.edu

EDUCATION:

University of Wisconsin, 1974; Experimental Oncology (Ph.D.)

German Cancer Research Institute, Heidelberg, Germany, 1974-1976 (Postdoctoral Fellow)

National Cancer Institute, Bethesda, Maryland, 1976-1978 (Staff-Fellow)

HONORS/AWARDS:

Chair, Cancer Biology Graduate Interdisciplinary Program, 1998-present

Recipient, Eleanor Roosevelt Fellowship

Chair, Chemical Pathology Study Section, National Institutes of Health, 1986-1988

Member, Board of Scientific Counselors, Division of Biometry and Risk Assessment, NIEHS, 1989-1993

Reviewer, American Cancer Society, Carcinogenesis, Nutrition and the Environmental Study Panel, 1992-1996

Chair, American Cancer Society, Carcinogenesis, Nutrition and the Environment Study Panel, 1/1997-present
Sydney Salmon Award forDistinguished Senior Investigator , 2006

Fellow, American Association for the Advancement of Science, 2006

MAJOR AREAS OF RESEARCH INTEREST:

Molecular mechanisms of radiation and chemical carcinogenesis, chemoprevention of cancer. My research involves studies of gene alterations that occur during multistage development of cancers. I am also studying the functional role of these gene changes in the development of cancers. It is through these basic studies that we are collaborating with clinical scientists in developing new strategies in the chemoprevention of human cancer.A major focus of our research is on a class of proto-oncogenes that encode for transcription factors of the jun and fos families. These encoded proteins bind to each other (i.e., Jun-Jun or Jun-Fos dimers) to form a transcription factor complex called "activator complex 1" or AP-1. AP-1 is known to bind and transactivate genes that are involved in cell growth and tumor cell invasion. It has been shown that repeated, transient activation of AP-1 plays a role in tumor promotion and our laboratory has obtained evidence that sustained AP-1 activity plays a role in the maintenance of the malignant phenotype. In the case of tumor promotion, repeated activation of AP-1 may lead to sustained cell proliferation and constitutive AP-1 activity in malignant cells could lead to invasive and metastatic phenotypes.Our studies of AP-1 in tumor promotion and progression are carried out in a mouse skin model of multistage carcinogenesis. We have been investigating mechanisms whereby the skin tumor promoting agent, okadaic acid, a phosphatase inhibitor, mediates AP-1 activation in mouse keratinocytes. We found that the okadaic acid increase in AP-1 DNA binding was through increased expression junB, junD and fosB. This increase in expression was, in part, through transcriptional activation of the jun and fos genes. We are studying the transcriptional regulation of the junB by okadaic acid. We are also investigating the mechanism whereby in malignant progression there is increased AP-1 activity. In a mouse keratinocyte model of progression we have obtained evidence that down-regulation of expression of the junB gene may play a functional role in up regulation of AP-1 activity. We are presently investigating the mechanism for down regulated expression of the junB. In a collaborative effort we have been investigating UVB induced signal transduction in keratinocytes leading to AP-1 activation. We have demonstrated that UVB induced AP-1 activation is mediated through activation of sphingomyelinase and atypical PKC. We have also found that certain natural products, perillyl alcohol and epigallo-catechin-gallate block UVB induced AP-1 activation. These agents have been shown to inhibit UVB induced mouse skin carcinogenesis. These agents will be tested in human clinical trials for chemporeventive activity.

Finally, in a collaborative effort we have been investigating paracrine regulation of the matrix metalloproteinase, matrilysin, in human prostate tumor cells. We have demonstrated that interleukin-1 can transcriptionally up regulate the expresison of matrilysin in prostate tumor cells. We are also planning to isolate and characterize a paracrine factor from prostate fibroblasts that induces expression of matrilysin in the same cells.

STUDENT OPPORTUNITIES THROUGH RESEARCH:

Medical students can participate in bench research related to regulation of the transcriptional factor complex, AP-1, in cultured keratinocytes by the tumor promoter, okadaic acid. They can work on the problem of why JunB protein is downregulated in the progression of benign to malignant epidermal cells. A student could investigate the mechanism(s) by which perillyl alcohol or EGCG inhibit UVB-induced AP-1 activity. Finally, a student could help in the purification and characterization of a paracrine factor from prostate fibroblasts that induces matrilysin expression in prostate carcinoma cells.

Last updated: 11/28/2006