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.
Any link on the below references will take you off
of the BMCB site and to an abstract of that particular paper.
Catania, J.M., A.R. Parrish, D.S. Kirkpatrick, M. Chitkara, G.T.
Bowden, C.J. Henderson, C.R. Wolf, A.J. Clark, K. Brendel, R.L. Fisher,
and A.J. Gandolfi. 2003. Precision-cut tissue slices from transgenic
mice as an in vitro toxicology system. Toxicology
In Vitro 17: 201-205.
Bair, W.B. 3rd, N. Hart, J. Einspahr, G. Liu, Z. Dong, D. Alberts,
and G.T. Bowden. 2002. Inhibitory effects of sodium salicylate and
acetylsalicylic acid on UVB-induced mouse skin carcinogenesis. Cancer
Epidemiology Biomarkers and Prevention 11: 1645-1652.
Thompson, E.J., A. Gupta, M.S. Stratton, and G.T. Bowden. 2002. Mechanism
of action of a dominant negative c-jun mutant in inhibiting activator
protein-1 activation. Molecular
Carcinogenesis 35: 157-162.
Bachelor, M.A., A.L. Silvers, and G.T. Bowden. 2002. The role of
p38 in UVA-induced cyclooxygenase-2 expression in the human keratinocyte
cell line, HaCaT. Oncogene 21: 7092-7099.
Stratton, M.S., B. Greenstein, T.S. Udayakumar, R.B. Nagle, and G.T.
Bowden. 2002. Androgens block interleukin-1 beta-induced promatrilysin
expression in prostate carcinoma cells. Prostate 53: 1-8.
Gonzales, M., and G.T. Bowden. 2002. UVB induction of the c-fos promoter
is mediated by phospho-CREB binding to CRE and FAP1 cis elements. Gene 293: 169-179.
Thompson, E.J., J. MacGowan, M.R. Young, N. Colburn, and G.T. Bowden.
2002. A dominant negative c-jun specifically blocks okadaic acid-induced
skin tumor promotion. Cancer
Research 62: 3044-3047.
Gonzales, M., and G.T. Bowden. 2002. The role of PI 3-kinase in the
UVB-induced expression of c-fos. Oncogene 21: 2721-2728.
Udayakumar, T.S., M.S. Stratton, R.B. Nagle, and G.T. Bowden. 2002.
Fibroblast growth factor-1 induced promatrilysin expression through
the activation of extracellular-regulated kinases and STAT3. Neoplasia 4: 60-67.
Bair, E.L., N. Tran, C.P. Massey, A.H. Borchers, R.L. Heimark, A.E.
Cress, and G.T. Bowden. 2001. 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.
Tang, Q., W. Chen, M.S. Gonzales, H. Inoue, and G.T. Bowden. 2001.
Role of cyclic AMP responsive element in the UVB induction of cyclooxygenase-2
transcription in human keratinocytes. Oncogene 20: 5164-5172.
Thompson, E.J., A. Gupta, G.A. Vielhauer, J.W. Regan, and G.T. Bowden.
2001. The growth of malignant keratinocytes depends on signaling via
the PGE2 receptor RP11. Neoplasia 3 :402-410.
