The objective is to investigate the biochemical and molecular mechanisms that regulate expression of specific differentiated functions in a model system of dispersed cells in culture. Studies will focus on: 1. Analyis of the acute actions of a regulatory peptide: thyrotropin-releasing hormone (TRH) as a prototype. Experiments will use clonal strains of pituitary cells and will examine the nature of the biochemical linkage between the TRH receptor and polyphosphatidylinositol hydrolysis, the mechanisms used by the cell for mobilization of intracellulr Ca2+, characterization of membrane cation channels, and the roles of protein kinase C and protein phosphorylation in acute actions of TRH on hormone (prolactin (PRL) and growth hormone (GH)) secretion. 2. Actions of tumor-promoting phorbol esters on differentiated functions. Phorbol esters will be localized in cells by a new immunohistochemical approach, and the mechanisms by which phorbol esters modulate plasma membrane receptors and regulate acute protein secretion (PRL and GH) will be investigated. 3. Regulation of specific protein synthesis. Using a highly differentiated cell culture system in which the biosynthesis of PRL and GH is controlled by hormones, Ca2+, and tumor promoters, I shall investigate the biochemical and molecular mechanisms by which phorbol esters and TRH regulate the biosynthesis of PRL and GH, and the role of Ca2+ in the regulatory pathway. The results of these studies will contribute new knowledge on the details of regulation of 2 important protein hormones; this fundamental knowledge can be expected to contribute to the better understanding of certain disorders of growth (including cancer) and reproductive function.
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