The alpha-subunit gene of the hunman glycoprotein hormones is expressed as a component of three pituitary hormones (luteinizing hormone and follicle-stimulating hormone in gonadotropes and thyroid-stimulating hormone in thyrotropes), and one placental hormone (chorionic gonadotropin). Each hormone shares a single common alpha-subunit gene, and has an independent beta-subunit gene. These hormones are both developmentally and hormonally regulated and are tissue specific. Production of the alpha subunit is regulated independently in each cell type, in coordination with the beta subunit with which it becomes associated. The pituitary hormones are positively controlled by hypothalamic releasing hormones and negatively controlled by steroid and thyroid hormones. Chorionic gonadotropin in the placenta is regulated by developmental and autocrine and/or paracrine factors. Thus, the alpha-subunit gene contains regulatory sequences which direct expression in several tissues at different stages of development and facilitate its differential hormonal responsiveness. We have identified and characterized the mechanisms of action of several control elements involved in regulation of the alpha- subunit gene using gene transfer into cultured cells and transgenic mice. These studies have provided detailed information concerning tissue-specific control, the mechanism of negative regulation by steroids and the actions of the second messenger, cAMP; in addition to pituitary specificity and oncogenesis. These elements and enhancers appear to interact by novel mechanisms including synergism, interference, and modification of their transactivating proteins. In the proposed studies, we hope to gain a more detailed understanding of the mechanisms of action of the elements defined to date and identify and study additional elements and factors that may participate in the hormonal regulation and tissue-specific control of this gene. The levels of regulation to be investigated include placental specificity, second messenger activation, steriod and thyroid hormone regulation and pituitary specificity. We will continue to rely on approaches in which genes are transfected into cells in culture, since these have been quite successful to date. In addition, we will increase our efforts with transgenic mice which in early studies have revealed important information and great promise.
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