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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 mouse and human keratinocytes leading to AP-1 activation and enhanced expression of cyclo-oxygenase-2 gene (COX-2). 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 found that UVB mediates AP-1 activation and COX-2 expression through two signaling pathways, p38 MAP kinase and PI-3 kinase. We also have found that certain natural products, perillyl alcohol and epigallocatechin-gallate, block UVB-induced signaling pathways leading to AP-1 activation and COX-2 expression. These agents have been shown to inhibit UVB-induced mouse skin carcinogenesis and will be tested in human clinical trials for chemopreventive activity. We have investigated UVA induced anti-apoptotic signaling involving the Bcl-XL protein in keratinocytes. We found that UVA induces the stabilization of the Bcl-XL mRNA through the 3’UTR and ARE sites within this region of the mRNA.
Finally, in a collaborative effort, we investigated paracrine regulation of the matrix metallo-proteinase (MMP), matrilysin, in human prostate tumor cells. We demonstrated that interleukin-1 and fibroblast growth factor can transcriptionally up-regulate the expression of matrilysin in prostate tumor cells. We also investigated the cleavage of certain laminin proteins (i.e. laminins 5 and 10) located in the prostate by the trans-membrane MMP, MT1-MMP, which is overexpressed in prostate cancer. We found that cleavage of both laminins by MT1-MMP enhances the migration of prostate carcinoma cells.