Irving Boime

Human chorionic gonadotropin (CG), lutropin (LH), follitropin (FSH), and thyrotropin (TSH) are a family of heterodimeric glycoprotein hormones that share a common α subunit but differ in their hormone-specific β subunits. One or more of these hormones is essential for gonadal development, and for maintaining pregnancy and thyroid function. Using site-directed mutagenesis, our laboratory investigates structural determinants that govern the unique post-translational modifications of the related placental and pituitary glycoprotein hormones. These hormones undergo specific modifications and have unique biologic activities. Together with DNA mediated transfection techniques, monoclonal antibody screening, and protein and carbohydrate characterization, the laboratory is examining the regions critical for chaperone interactions in the folding and the differential sorting of these heterodimeric hormones. Studies are also underway for determining the ligand determinants that are responsible for the transducing signals in the hormone-receptor complex. A critical feature of these hormones is their unique secretion patterns. LH is secreted through a regulated secretory pathway, i.e. it is released by secretagogue, whereas FSH is primarily secreted constitutively. The oligosaccharides on these glycoproteins are hormone specific. We are currently testing models addressing the hypothesis that the carbohydrates play a critical role in FSH/LH sorting. FSH-LH β chimeras and point mutants are currently designed to identify sequences that govern their unique secretion patterns. Informative LH and FSH variants in cell-culture assays will be expressed in pituitaries from transgenic mice. The ability to reroute FSH and LH in vivo would represent an important model for gonadal dysfunction and potentially provide a novel way to examine normal and ultimately pathophysiological events in the human reproductive tract.

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