UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

We study the activity of the intracellular receptors (IRs) in signal transduction and transcriptional control, including receptors for glucocorticoids (GR), androgens (AR), and thyroid hormone (TR).These hormone-receptor complexes bind to specific DNA sequences termed hormone response elements, which enhance or repress linked promoters.

We have defined IR domains for hormone and DNA binding, dimerization, nuclear localization, phosphorylation, interaction with various cellular factors and transcriptional regulation. IRs function faithfully when expressed in simpler organisms such as yeast and Drosophila, thus facilitating genetic analyses of their actions and identification of other factors involved in their activities. We are also pursuing 3D-structure analyses of various domains of the receptor, and we employ biochemical strategies with purified components for mechanistic analyses. Thus, using genetic, structural, molecular and biochemical approaches, we use IRs as biological probes to define how a single regulatory protein can specify diverse patterns of specific gene expression in different cellular contexts.

These strategies can increasingly be applied to studies of complex physiological and pathological processes. Thus, we are pursuing: (a) a signaling crosstalk pathway in developing T-cells in which activation of the T-cell receptor abrogates glucocorticoid-induced apoptosis; (b) dramatic shifts in AR activity and ligand responses during prostate cancer ontogeny and progression; (c) the consequences of glutamine repeat expansion in AR, leading to motor neuron degeneration in spinal and bulbar muscular atrophy.

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