G. Timothy Bowden,
Professor of Radiation Oncology, Ph.D., University of Wisconsin, Madison, 1974
tbowden@azcc.arizona.edu

Molecular aspects of chemical and physical carcinogenesis, mechanisms of oncogene activation and signal transduction pathways

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.

Publications (Query PubMed for this investigator)

Gonzales, M. and Bowden, G.T. UVB induction of the c-fos promoter is mediated by phospho-CREB binding to CRE and FAP1 cis elements. Gene, 293:169-179, 2002.

Thompson EJ, MacGowan J, Young MR, Colburn N and Bowden GT. A dominant negative c-jun specifically blocks okadaic acid-induced skin tumor promotion. Cancer Research, 62(11):3044-7, 2002.

Gonzales, M. and Bowden, G.T. The role of PI 3-kinase in the UVB-induced expression of c-fos. Oncogene, 21:2721-2728, 2002.

Udayakumar, T.S., Stratton, M.S., Nagle, R.B. and Bowden, G.T. Fibroblast growth factor-1 induced promatrilysin expression through the activation of extracellular-regulated kinases and STAT3. Neoplasia 4(1):60-67, 2002.

Bair, E.L., Tran, N., Massey, C.P., Borchers, A.H., Heimark, R.L., Cress, A.E., Bowden, G.T. Integrin and cadherin mediated induction of the matrix metalloprotease matrilysin in co-cultures of malignant oral squamous cell carcinoma cells and dermal fibroblasts. Experimental Cell Research, 270:259-267, 2001.

Tang Q., Chen W., Gonzales, M.S., Inoue, H., Bowden, G.T. Role of cyclic AMP responsive element in the UVB induction of cyclooxygenase-2 transcription in human keratinocytes. Oncogene, 20:5164-5172, 2001.

Thompson E.J., Gupta A., Vielhauer G.A., Regan J.W., Bowden G.T. The growth of malignant keratinocytes depends on signaling via the PGE2 receptor RP11. Neoplasia, 3:402-410, 2001.

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