William Lee Kraus, Ph.D.

Pharmacology

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Adjunct Assistant Professor of Pharmacology.

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Biochemistry of Estrogen-Regulated Gene Transcription

The research in my laboratory includes two primary areas of investigation. They are: (1) mechanisms of signal transduction by nuclear hormone receptors and their associated cofactors, and (2) mechanisms of transcriptional activation with chromatin templates. My research is focused on the basic biochemistry and molecular biology of these processes, but I am also interested in how these areas of basic research relate to human diseases, especially cancer.
Lipophilic hormones, which include steroid hormones (e.g., estrogens, androgens, glucocorticoids) and vitamin hormones (e.g., vitamin D and the vitamin A derivative retinoic acid), act as effectors in intracellular signal transduction pathways. These hormones are delivered in the blood to target tissues where they pass through the cell membrane and bind to receptors located in the nuclei of cells. The receptors for these hormones (e.g., estrogen receptors and retinoic acid receptors) belong to a large 'superfamily' of evolutionarily conserved nuclear receptor proteins that function as ligand-regulated, DNA-binding transcriptional activators.
Eukaryotic transcriptional activators, including the nuclear hormone receptors, control the transcription of specific genes by RNA polymerase II in the chromatin environment of the nucleus. Transcriptional activators act in conjunction with transcriptional coactivator proteins (e.g., p300/CBP and SRC family members) to relieve the transcriptional repression caused by the packaging of target DNA templates into nucleosomes (i.e., chromatin). The relief of chromatin-mediated transcriptional repression and subsequent transcriptional activation may be achieved through a number of mechanisms. For example, covalent modification of chromatin proteins (e.g., the acetylation of lysine residues in the amino-terminal tails of the core histones) is thought to open chromatin structure, leading to greater access of the transcriptional machinery to the DNA template and increased transcriptional activation. Chromatin remodeling complexes (e.g., SWI/SNF) have also been implicated in the transcription of genes packaged as chromatin. In addition, protein-protein interactions among transcriptional activators, coactivators, and the basal transcriptional machinery are also thought to be important for transcriptional activation with chromatin templates.

My laboratory uses the tools of biochemistry and molecular biology to study the mechanisms of ligand- and cofactor-regulated transcription by RNA polymerase II with chromatin templates. We use in vitro chromatin assembly and transcription systems
with purified recombinant nuclear hormone receptor and coactivator proteins. These in vitro experiments are complemented by a variety of cell-based studies to understand more clearly how transcriptional activation by nuclear hormone receptors and coactivators occurs with genes packaged into chromatin inside the cell

For further information, see the Kraus Lab.

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Recent Publications

Lee, K.C. and Kraus, W.L. Nuclear receptors, coactivators and chromatin: new approaches, new insights. Trends Endocrin. Metab. 12: 191-197, 2001.

Kim, M.Y., Hsiao, S.J., Kraus, W.L. A role for coactivators and histone acetylation in estrogen receptor a-mediated transcription initiation. EMBO J. 20: 6084-6094, 2001.

Georges, S., Kraus W.L., Luger, K., Nyborg, J.K., Laybourn, P.J., p300-mediated Tax transcription from recombinant chromatin: histone tail deletion mimics coactivator function. Mol. Cell Biol. 22: 127-137, 2002.

Cheung, E., Zarifyan, A., Kraus, W.L. Histone H1 represses estrogen receptor transcriptional activity by selectively inhibiting receptor-mediated transcription initiation. Mol. Cell Biol. 22: 2463-2471, 2002.

Kraus, W.L. and Wong, J. Nuclear receptor-dependent transcription with chromatin: is it all about enzymes? Eur. J. Biochem. 269: 2275-2283, 2002.