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Sex steroids play a central role in the growth and maintenance of a number of tissues and the tumors originating from these tissues. Steroids of the glucocorticoid class control many aspects of metabolism and homeostasis. They have potent anti-inflammatory activities and are widely used in medicine. Steroid hormones achieve these wide ranging actions by regulating gene expression. The hormones bind to specific receptors which, via a series of events, become active transcription factors. The receptors for progesterone, a sex steroid, and cortisol, a glucocorticoid, are related. Indeed, the two receptors bind to the same target sequences in DNA.

How do the two receptors mediate the regulation of distinct sets of genes in tissues that contain both receptors? One area of research in the laboratory is directed to understanding the mechanisms of differential regulation of gene expression by these two receptors. Our studies have shown that a steroid-regulated promoter, the mouse mammary tumor virus promoter, is regulated very differently when integrated into different sites in the genome. This implies that the surrounding chromatin imposes differential regulation on the transcription control elements of this promoter. We are investigating the mechanistic basis by which chromatin structure influences steroid-mediated regulation of gene expression.

We are also investigating other mechanisms that regulate the transcriptional activity of steroid receptors. Receptor-mediated transcription can be either potentiated or suppressed by the activation of cellular signal transduction pathways that act via protein phosphorylation. We have shown, however, that phosphorylation of the glucocorticoid receptor is not changed under these conditions. Therefore, we have proposed that the coupling of phosphorylation-dependent cellular signal transduction pathways with steroid response mechanisms occurs through an intermediate such as a transcriptional coactivator. We are currently employing molecular and genetic strategies to test this hypothesis and identify the factors involved in regulating steroid induced gene expression.