The steroid hormones (estrogen and progesterone) stimulate growth, maturation and the development of new biochemical capacities in their endocrine target organs. Although it is widely accepted that steroid hormones exert major influences on the transcriptional process and induce gene activation, the detailed mechanisms of action of the receptors and their associated coregulator proteins are not yet defined in precise detail. The general objectives of our studies are to define the mechanism of action of steroid hormones and their receptors in regulating morphologic differentiation and biochemical specialization in target tissues. This will be accomplished by coordinating a network of investigations designed to uncover the mechanisms by which steroid receptors interact with nuclear coactivator proteins to mediate their effects on expression of protein products from target genes. We will emphasize experimental dissection of the coactivator's role in modulating initiation of transcription, alternative RNA processing, and importantly, in communicating signals to the genome from membrane receptors via intracellular signaling cascades and pathways. In addition, we must understand the role of sequential actions of distinct multiple high molecular weight coactivator complexes in the various substeps of nuclear receptor regulation of gene transcription. Finally, we will investigate the mechanisms by which specific steroid receptors accumulate coactivators at target promoters in a gene and cell specific manner to carry out these functions. These studies will involve aspects of nucleic acid and protein biochemistry, molecular biology, cell biology, endocrinology, and molecular endocrinology. It is expected that the understanding derived from this project will be relevant to the actions of the natural steroid hormones as well as selective receptor modulator drugs in human physiology. The following proposed studies should also be pertinent to development of more precise theories for the biochemical mechanism of action of intracellular hormones and receptors in general.
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