FUNCTION
AND REGULATION OF HUMAN GLUCOCORTICOID RECEPTORS
The transcriptional regulation controlled in eukaryotes is controlled by various sequence-specific DNA-binding proteins, many of which have been identified. Variation in gene expression is achieved by modulating the activity of protein factors.Depending on the cell type, glucocorticoids and its receptor, GR, have diverse functions, which include anti-inflammation, anti-allergic and antidepressant properties. Our research is centered on the identification of the steps involved in the regulation of the GR gene.
In prostate cancer, cells that respond to antiandrogen treatment initially become unresponsive. The precise mechanism by which this switch occurs is unknown. The androgen receptor (AR) via its ligand, plays a crucial role in this switch. We are primarily interested in isolating factors that interact with the N-terminal AF-1 region of the AR.
Studies with the mineralocorticoid receptor (MR) have shown similarities and differences with the GR. Mineralocorticoids, under the control of the renin-angiotensin system, are involved in the homeostasis of electrolyte balance principally in the kidney. A malfunction can lead to hypertension. We are presently able to identify the N-terminal regions in the MR that are involved in transcriptional activity. Our goal is to isolate factors that determine the tissue specificity of MR expression.
Using recombinant DNA techniques, gene transfer, yeast one-and two-hybrid systems to study protein-protein interaction, we hope to answer these questions. This approach will allow us to synthesize and analyze chemical substances that have potential antiglucocorticoid, antimineralocorticoid and antiandrogen properties.
These projects are supported by the Medical Research Council of Canada.
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Warriar N., Yu C. and M.V. Govindan (1994). Hormone binding domain of human glucocorticoid receptor: Enhancement of transactivation function by substitution mutants M565R and A573Q. J. Biol. Chem. 269: 290101-29015.
Yu C., Warriar N. and M.V. Govindan (1995). Cysteines 638 and 665 in the hormone binding domain fo the human glucocorticoid receptor define the specificity to glucocorticoids. Biochemistry 34: 14163-14173.
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