Lutropin (LH) and follitropin (FSH) are the pituitary gonadotropins which regulate sex-steroid hormone secretion and biosynthesis, and gametogenesis. In addition, LH and FSH are glycoprotein hormones that are synthesized and secreted by gonadotrope in the anterior pituitary gland, and are essential for normal sexual development and reproduction. Each hormone is composed of two different subunits, alpha and beta, which are encoded by separate genes located on different chromosomes. The long-term objective of this work is to understand how various hormones, including the newly described gonadal peptides, regulate the biosynthesis of LH and FSH at the pre- translational level. The key goal of this proposal is to characterize further hormonal regulation of expression of FSH subunit genes in the gonadotrope.
The Specific Aims are: (1) to determine the effects of inhibins, activins, and follistatins, and their interactions, on the biosynthesis of LH and FSH at the pre-translational level in cultured rat pituitary cells in the absence of GnRH; (2) to explore the effects of these gonadal peptidase in the presence of constant or pulsatile GnRH in static or perifused rat pituitary cells; (3) to elucidate molecular mechanisms by which steady-state FSH-beta mRNA levels are altered; (4) to identify critical cis-DNA elements, and subsequently related trans-acting factors, within the regulatory regions of the rat FSH-beta gene that mediate hormone responses, using reporter gene constructs and gene transfer in a transient expression assay; and (5) to establish permanent gonadotrope cell lines utilizing transgenic mouse models to induce specific gonadotrope tumors and retrovirus-mediated oncogene transduction of primary rat pituitary cultures, with subsequent selection of cell lines with hormone-regulated differentiated function. The pre-translational studies will involved determinations of steady-state levels of subunit mRNAs, transcriptional rates, and stability of subunit mRNAs. It is expected that such studies will allow a deeper understanding into the regulation of gonadotropin production at one of the major steps in the biosynthetic pathway, that is, the positive and negative effects of various hypothalamic and gonadal factors on gonadotropin subunit synthesis at the genomic level.
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