Our research effort is centered around the regulation of gene expression by coactivators and corepressors of transcription, and the functional interaction of these proteins with transcription factors and signal transduction pathways in the cell. We have identified the requirement for both “positive” and “negative” regulatory complexes in the activities of nuclear receptors and for other classes of transcription factors, and have shown that ligand-dependent transcriptional activation in many cases involves an exchange of a corepressor complex containing histone deacetylase activates for a coactivator complex containing at least one histone acetyltransferase. These complexes are also regulated at the level of phosphorylation, acetylation, and other forms of posttranslational modification, providing opportunity for complex, multifactorial regulation of genes in a manner that is highly sensitive to signals coming from outside of the cell. One application of this research has proven to be an improved understanding of the activities of nuclear receptor hormones and antagonists. For instance, the estrogen receptor antagonist tamoxifen is widely used in the treatment of breast cancer, but some ER positive tumors do not respond well or become resistant to tamoxifen treatment over a period of time. While much is known about the mechanisms by which tamoxifen and other Selective Estrogen Receptor Modulators (SERMs) affect the function of ER, the molecular basis of tamoxifen resistance remains unclear and represents an important and clinically relevant problem. We have shown that the antagonistic properties of tamoxifen and other nuclear receptor antagonists require the functional activity of a nuclear receptor corepressor complex, which is in turn responsive to the activation of signaling pathways associated with growth and inflammation. Continued work in this area will provide further insight into the molecular mechanisms underlying these regulatory schemes.
We are also interested in the mechanisms underlying the inflammatory response in endothelial tissues. It has been known for some time that the activities of some proinflammatory cytokines such as tumor necrosis factor are largely mediated by intracellular signaling pathways that lead to the activation of the transcription factor NFkB. We are studying regulation of this important gene expression response in endothelial cells, and have found that the activity of NFkB is also responsive to corepressor/coactivator exchange. The expression of several adhesion molecules that participate in the inflammatory response is regulated by a combination of multiple transcription factors, exchange of regulatory factors, and movement of proteins from one compartment to another, all of which is responsive to signaling pathways. Our work in this area is intended to better understand the dynamic interface provided by the vascular endothelium between the circulating blood and the underlying smooth muscle cells.