G. Timothy Bowden
Wisconsin-Madison.
Professor of Cell Biology and Anatomy, Pharmacology and Toxicology, & Molecular and Cellular Biology
Chair, Cancer Biology Graduate Interdisciplinary Program
e-mail: tbowden@azcc.arizona.edu
Research: Molecular mechanisms of physical and chemical carcinogenesis; cellular oncogene activation and differential gene expression during tumor progression.
Summary of Research Activities
My research involves studies of gene alterations that occur during multistage development of cancers. We also are studying the functional role of these gene changes in the development of cancers. Through these basic studies, we are collaborating with clinical scientists to develop new strategies for 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. 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 of 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 also have demonstrated that AP-1- mediated transcriptional activation is through altered phosphorylation of JunD and FosB proteins.
In a collaborative effort, we have been investigating UVB-induced signal transduction in human keratinocytes leading to AP-1 activation. We have demonstrated that UVB-induced AP-1 activation is mediated through increased binding of JunD and c-Fos to AP-1 consensus DNA sequence. We also have found that certain natural products, perillyl alcohol and epigallocatechin-gallate, block UVB-induced AP-1 activation. These agents have been shown to inhibit UVB-induced mouse skin carcinogenesis and will be tested in human clinical trials for chemopreventive activity.
Finally, in a collaborative effort, we have been investigating paracrine regulation of the matrix metallo-proteinase, matrilysin, in human prostate tumor cells. We have demonstrated that interleukin-1 and fibroblast growth factor can transcriptionally up-regulate the expression of matrilysin in prostate tumor cells. We also are investigating differential expression of fibroblast growth factor receptors in normal- and carcinoma-derived prostate epithelial cells.
Selected Publications
Udayakumar TS, Chen ML, Bair EL, Cress AE, Nagle RB and Bowden GT. MT1-MMP expressed by prostate carcinoma cells cleaves human laminin-5 b3 chain and induces cell migration. Cancer Research, 63(9):2292-9, 2003.
Cooper SJ, MacGowan J, Ranger-Moore J, Young MT, Colburn NH and Bowden GT. Expression of dominant negative c-jun inhibits UVB induced squamous cell carcinoma number and size in an SKH-1 hairless mouse model. Molecular Cancer Research 1:848-854, 2003.
Kwei KA, Finch JS, Thompson EJ, and Bowden GT. Transcriptional repression of catalase in mouse skin tumor progression. Neoplasia, 6(5):440-448, 2004.
Collaborative Research
Zigang Dong, Ph.D., Hormel Institute, University of Minnesota, Austin, Minnesota: UVB signal transduction.
David S. Alberts, M.D., Internal Medicine: chemoprevention of human skin cancer.
Raymond Nagle, M.D., Ph.D., Pathology: matrix metalloproteinases and human prostate cancer.
