Molecular structure of the human gonadotropin-releasing hormone receptor gene

Department of Physiology and Biophysics, University of Alabama at Birmingham 35294-0005, USA.

GnRH receptors belong to the family of G protein-coupled receptor proteins and have been localized to the anterior pituitary, brain and reproductive organs as well as many steroid-dependent tumor tissues. Recently, cDNAs for the GnRH receptors of several species including the human have been cloned. To determine the structure of the gene encoding the human GnRH receptor, we isolated the receptor gene clones from the human genomic libraries. Comparison of the genomic and cDNA sequences revealed that the human GnRH receptor gene is composed of three exons and two introns and spans over 20 kb in size. Exon 1 encodes the 5' untranslated sequence and nucleotide +1 to +522 in the open reading frame, exon 2 encodes nucleotide +523 to +742 and exon 3 encodes nucleotide +743 to +987 in the open reading frame as well as the 3' untranslated sequence. Southern blot analysis of genomic DNA and localization of the GnRH receptor gene to a single site on human chromosome 4 (4q13) indicate the presence of a single copy of the gene in the human genome. Several regulatory sequences for various hormones and other regulatory factors were identified, including PEA-3, AP-1, AP-2, and Pit-1 sites. In addition, glucocorticoid/progesterone response element thyroid hormone response element, and cAMP response element sequences were identified. Reverse transcriptase-primer extension and 5' RACE analysis of the human pituitary RNA demonstrated the presence of multiple transcriptional start sites upstream of the translational start site. Analysis of the 5' flanking region of the gene also revealed the presence of multiple TATA and CAAT sequences. The finding of multiple transcriptional start sites raises the possibility of tissue-specific regulation and the existence of variable size transcripts. Chimeras containing 1.26 kb (-534 to 728) of the 5' flanking region of the receptor gene and the luciferase (Luc) gene expressed a significant luciferase activity when transfected into a human endometrial tumor cell line (HEC-1A) and a breast tumor cell line (MCF-7) but not in a mouse pituitary gonadotrope cell line (alpha T3-1), suggesting the existence of multiple promoter elements in the gene. These findings indicate a multiplicity of regulation of expression of the GnRH receptor and provide the substrate for detailed investigation in the reproductive system.

This article has been cited by other articles:

				C. Metallinou, B. Asimakopoulos, A. Schroer, and N. Nikolettos Gonadotropin-Releasing Hormone in the Ovary Reproductive Sciences, December 1, 2007; 14(8): 737 - 749. [Abstract] [PDF]

				M. Shimizu and G. Y. Bedecarrats Identification of a Novel Pituitary-Specific Chicken Gonadotropin-Releasing Hormone Receptor and Its Splice Variants Biol Reprod, November 1, 2006; 75(5): 800 - 808. [Abstract] [Full Text] [PDF]

				A. Granger, C. Bleux, M.-L. Kottler, S. J. Rhodes, R. Counis, and J.-N. Laverriere The LIM-Homeodomain Proteins Isl-1 and Lhx3 Act with Steroidogenic Factor 1 to Enhance Gonadotrope-Specific Activity of the Gonadotropin-Releasing Hormone Receptor Gene Promoter Mol. Endocrinol., September 1, 2006; 20(9): 2093 - 2108. [Abstract] [Full Text] [PDF]

				C.-M. Yeung, B.-S. An, C. K. Cheng, B. K.C. Chow, and P. C.K. Leung Expression and transcriptional regulation of the GnRH receptor gene in human neuronal cells Mol. Hum. Reprod., November 1, 2005; 11(11): 837 - 842. [Abstract] [Full Text] [PDF]

				N. Moncaut, G. Somoza, D. M Power, and A. V M Canario Five gonadotrophin-releasing hormone receptors in a teleost fish: isolation, tissue distribution and phylogenetic relationships J. Mol. Endocrinol., June 1, 2005; 34(3): 767 - 779. [Abstract] [Full Text] [PDF]

				C. K. Cheng and P. C. K. Leung Molecular Biology of Gonadotropin-Releasing Hormone (GnRH)-I, GnRH-II, and Their Receptors in Humans Endocr. Rev., April 1, 2005; 26(2): 283 - 306. [Abstract] [Full Text] [PDF]

				A. Ulloa-Aguirre, J. A. Janovick, A. Leanos-Miranda, and P. M. Conn Misrouted cell surface GnRH receptors as a disease aetiology for congenital isolated hypogonadotrophic hypogonadism Hum. Reprod. Update, March 1, 2004; 10(2): 177 - 192. [Abstract] [Full Text] [PDF]

				A. Granger, V. Ngo-Muller, C. Bleux, C. Guigon, H. Pincas, S. Magre, D. Daegelen, A. Tixier-Vidal, R. Counis, and J.-N. Laverriere The Promoter of the Rat Gonadotropin-Releasing Hormone Receptor Gene Directs the Expression of the Human Placental Alkaline Phosphatase Reporter Gene in Gonadotrope Cells in the Anterior Pituitary Gland as well as in Multiple Extrapituitary Tissues Endocrinology, February 1, 2004; 145(2): 983 - 993. [Abstract] [Full Text] [PDF]

				C. K. Cheng, B. K. C. Chow, and P. C. K. Leung An Activator Protein 1-Like Motif Mediates 17{beta}-Estradiol Repression of Gonadotropin-Releasing Hormone Receptor Promoter via an Estrogen Receptor {alpha}-Dependent Mechanism in Ovarian and Breast Cancer Cells Mol. Endocrinol., December 1, 2003; 17(12): 2613 - 2629. [Abstract] [Full Text] [PDF]

				H. Sadie, G. Styger, and J. Hapgood Expression of the Mouse Gonadotropin-Releasing Hormone Receptor Gene in {alpha}T3-1 Gonadotrope Cells Is Stimulated by Cyclic 3',5'-Adenosine Monophosphate and Protein Kinase A, and Is Modulated by Steroidogenic Factor-1 and Nur77 Endocrinology, May 1, 2003; 144(5): 1958 - 1971. [Abstract] [Full Text] [PDF]

				R. L. C. Hoo, E. S. W. Ngan, P. C. K. Leung, and B. K. C. Chow Two Inr Elements Are Important for Mediating the Activity of the Proximal Promoter of the Human Gonadotropin-Releasing Hormone Receptor Gene Endocrinology, February 1, 2003; 144(2): 518 - 527. [Abstract] [Full Text] [PDF]

				L. F. G. Silveira, P. M. Stewart, M. Thomas, D. A. Clark, P. M. G. Bouloux, and G. S. MacColl Novel Homozygous Splice Acceptor Site GnRH Receptor (GnRHR) Mutation: Human GnRHR "Knockout" J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2973 - 2977. [Abstract] [Full Text] [PDF]

				L. Wang, D. Y. Oh, J. Bogerd, H. S. Choi, R. S. Ahn, J. Y. Seong, and H. B. Kwon Inhibitory Activity of Alternative Splice Variants of the Bullfrog GnRH Receptor-3 on Wild-Type Receptor Signaling Endocrinology, September 1, 2001; 142(9): 4015 - 4025. [Abstract] [Full Text] [PDF]

				S. J. Winters, S. Kawakami, A. Sahu, and T. M. Plant Pituitary Follistatin and Activin Gene Expression, and the Testicular Regulation of FSH in the Adult Rhesus Monkey (Macaca mulatta) Endocrinology, July 1, 2001; 142(7): 2874 - 2878. [Abstract] [Full Text] [PDF]

				K. W. Cheng, B. K. C. Chow, and P. C. K. Leung Functional Mapping of a Placenta-Specific Upstream Promoter for Human Gonadotropin-Releasing Hormone Receptor Gene Endocrinology, April 1, 2001; 142(4): 1506 - 1516. [Abstract] [Full Text]

				H. Pincas, K. Amoyel, R. Counis, and J.-N. Laverrière Proximal cis-Acting Elements, Including Steroidogenic Factor 1, Mediate the Efficiency of a Distal Enhancer in the Promoter of the Rat Gonadotropin-Releasing Hormone Receptor Gene Mol. Endocrinol., February 1, 2001; 15(2): 319 - 337. [Abstract] [Full Text]

				K. W. Cheng, E. S. W. Ngan, S. K. Kang, B. K. C. Chow, and P. C. K. Leung Transcriptional Down-Regulation of Human Gonadotropin-Releasing Hormone (GnRH) Receptor Gene by GnRH: Role of Protein Kinase C and Activating Protein 1 Endocrinology, October 1, 2000; 141(10): 3611 - 3622. [Abstract] [Full Text] [PDF]

				M.-L. Kottler, S. Chauvin, N. Lahlou, C. E. Harris, C. J. Johnston, J.-P. Lagarde, P. Bouchard, N. R. Farid, and R. Counis A New Compound Heterozygous Mutation of the Gonadotropin-Releasing Hormone Receptor (L314X, Q106R) in a Woman with Complete Hypogonadotropic Hypogonadism: Chronic Estrogen Administration Amplifies the Gonadotropin Defect J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3002 - 3008. [Abstract] [Full Text]

				K. W. Cheng, P. S. Nathwani, and P. C. K. Leung Regulation of Human Gonadotropin-Releasing Hormone Receptor Gene Expression in Placental Cells Endocrinology, July 1, 2000; 141(7): 2340 - 2349. [Abstract] [Full Text] [PDF]

				F. P. Pralong, F. Gomez, E. Castillo, S. Cotecchia, L. Abuin, M. L. Aubert, L. Portmann, and R. C. Gaillard Complete Hypogonadotropic Hypogonadism Associated with a Novel Inactivating Mutation of the Gonadotropin-Releasing Hormone Receptor J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3811 - 3816. [Abstract] [Full Text] [PDF]

				G. Maya-Núñez and P. M. Conn Transcriptional Regulation of the Gonadotropin-Releasing Hormone Receptor Gene Is Mediated in Part by a Putative Repressor Element and by the Cyclic Adenosine 3',5'-Monophosphate Response Element Endocrinology, August 1, 1999; 140(8): 3452 - 3458. [Abstract] [Full Text]

				E. R. Norwitz, K.-H. Jeong, and W. W. Chin Molecular Mechanisms of Gonadotropin-Releasing Hormone Receptor Gene Regulation Reproductive Sciences, July 1, 1999; 6(4): 169 - 178. [Abstract] [PDF]

				E. R. Norwitz, G. R. Cardona, K.-H. Jeong, and W. W. Chin Identification and Characterization of the Gonadotropin-releasing Hormone Response Elements in the Mouse Gonadotropin-releasing Hormone Receptor Gene J. Biol. Chem., January 8, 1999; 274(2): 867 - 880. [Abstract] [Full Text] [PDF]

				T.E. Adams, H. Sakurai, and B.M. Adams Effect of Stress-Like Concentrations of Cortisol on Estradiol-Dependent Expression of Gonadotropin-Releasing Hormone Receptor in Orchidectomized Sheep Biol Reprod, January 1, 1999; 60(1): 164 - 168. [Abstract] [Full Text]

				X. Lin and P. M. Conn Transcriptional Activation of Gonadotropin-Releasing Hormone (GnRH) Receptor Gene by GnRH and Cyclic Adenosine Monophosphate Endocrinology, September 1, 1998; 139(9): 3896 - 3902. [Abstract] [Full Text] [PDF]