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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA060871-04A2
Application #
2626822
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Mohla, Suresh
Project Start
1993-07-15
Project End
2002-01-31
Budget Start
1998-04-01
Budget End
1999-01-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Physiology
Type
Schools of Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Okada, Yohei; Murota-Kawano, Akiko; Kakar, Sham S et al. (2003) Evidence that gonadotropin-releasing hormone (GnRH) II stimulates luteinizing hormone and follicle-stimulating hormone secretion from monkey pituitary cultures by activating the GnRH I receptor. Biol Reprod 69:1356-61
Kakar, S S (1999) Molecular cloning, genomic organization, and identification of the promoter for the human pituitary tumor transforming gene (PTTG). Gene 240:317-24
Kakar, S S; Jennes, L (1999) Molecular cloning and characterization of the tumor transforming gene (TUTR1): a novel gene in human tumorigenesis. Cytogenet Cell Genet 84:211-6
Kakar, S S (1998) Inhibition of growth and proliferation of EcRG293 cell line expressing high-affinity gonadotropin-releasing hormone (GnRH) receptor under the control of an inducible promoter by GnRH agonist (D-Lys6)GnRH and antagonist (Antide). Cancer Res 58:4558-60
Kakar, S S (1998) Assignment of the human tumor transforming gene TUTR1 to chromosome band 5q35.1 by fluorescence in situ hybridization. Cytogenet Cell Genet 83:93-5
Kakar, S S; Nath, S; Bunn, J et al. (1997) The inhibition of growth and down-regulation of gonadotropin releasing hormone (GnRH) receptor in alphaT3-1 cells by GnRH agonist. Anticancer Drugs 8:369-75
Kakar, S S (1997) Molecular structure of the human gonadotropin-releasing hormone receptor gene. Eur J Endocrinol 137:183-92

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