Gonadotropin releasing hormone (GnRH), through its G-protein -coupled, high-affinity receptor located on gonadotropes of the anterior pituitary, stimulates the secretion of gonadotropins (LH and FSH). It is now known that GnRH receptors (GnRHR) are also present in extra pituitary tissues, hormone-responsive tumors and tumors derived cell lines, suggesting that GnRH may serve additional functions. GnRHR expression is highly regulated in exhibiting both up and down regulation by its cognate ligand, by gonadal steroids and peptides. However, the mechanisms involved in altering the rate of expression of the GnRHR at molecular levels is unknown. In order to understand the regulation of GnRHR gene expression in the pituitary, extra-pituitary tissues and hormone responsive tumors, the PI isolated the human GnRHR gene and defined its genomic organization. The human GnRHR gene is composed of two introns and three exons, and spans over 20 kb. It contains multiple transcriptional initiation sites and a large number of putative regulatory sequences for various hormones and other regulatory factors raising the possibility of tightly-regulated, differential expression of the receptor gene, which may be tissue specific. Thus the GnRHR may play a key role in the regulation of hormone-responsive tumors growth and its responsiveness to various stimuli and/or it's expression may be regulated by such stimuli. The long termed goals are to understand at the molecular level the DNA components and transcriptional factors that are responsible for the tissue specific expression and hormonal regulation of the human GnRHR gene, and to define the molecular mechanism of inhibition of tumor cell growth by GnRH.
The specific aims are: 1) To characterize the promoter sequence for GnRH-receptor gene in pituitary, extra-pituitary tissue and in hormone responsive tumors, 2) To study GnRHR, transcriptional regulation by estrogen, progesterone, glucocorticoid, testosterone, GnRH, inhibin, TPA and cAMP, 3) To identify the cells in tumors expressing GnRH receptor using a monoclonal antibody, and 4) To determine the expression of GnRH and GnRHR in normal and tumor tissues. These studies will likely provide a greater understanding of the regulation of the GnRH-receptor gene and allow us to better understand the complex mechanism of its transcriptional regulation. These studies have the potential to provide the basis for the development of a new class of drugs for treatments of hormone-responsive tumors.
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