David Rose

Affiliation: UCSD SOM

Associate Adjunct Professor in Medicine

Biography

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Research Summary

Our primary research interest is in the regulation of gene expression by cofactors of transcription, and the functional interaction of these proteins with transcription factors and signal transduction pathways in the cell. We have functionally characterized both 'positive' and 'negative' egulatory complexes in the regulation of nuclear receptors and other classes of transcription factors, and have shown that ligand-activated transcription in many cases involves an exchange of a corepressor complex containing histone deacetylase activities 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 work pertains to the mechanisms underlying the inflammatory response in endothelial tissues. 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. We are studying the regulation of the NFkB-mediated 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.

Another potential medical application of our studies pertains to the effectiveness of hormone antagonists used in cancer therapies. 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 affects the function of ER, the molecular basis of drug 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.

Our laboratory group has extensive experience in the microinjection of mammalian cells, followed by various forms of single cell analyses that permit interpretation of direct effects upon intracellular signaling pathways. Recently, we have made advances in the use of RNAi technology in connection with these microinjection experiments, and anticipate that this powerful technology when applied at the single cell level will allow studies of gene expression events that were not previously possible.

References

References From PubMed (NCBI)