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Endocrinology Vol. 139, No. 5 2443-2451
Copyright © 1998 by The Endocrine Society

ARTICLES

Identification of cis-Acting Deoxyribonucleic Acid Elements That Mediate Gonadotropin-Releasing Hormone Stimulation of the Rat Luteinizing Hormone ß-Subunit Gene1

Ursula B. Kaiser, Elena Sabbagh, Brian D. Saunders and William W. Chin

Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Dr. Ursula B. Kaiser, G. W. Thorn Research Building, Room 1009, Brigham and Women’s Hospital, 20 Shattuck Street, Boston, Massachusetts 02115. E-mail: kaiser{at}rascal.med.harvard.edu

GnRH plays a critical role in reproductive development and function by regulating the biosynthesis and secretion of the pituitary gonadotropins, LH and FSH. Although it is known that GnRH induces gonadotropin subunit gene transcription, the mechanism by which this occurs has not been elucidated. Studies have been hindered by the lack of available cell lines that express the LH and FSH subunit genes and respond to GnRH. We have transfected the rat pituitary GH3 cell line with the rat GnRH receptor complementary DNA. These cells, when cotransfected with regulatory regions of the LH or FSH subunit genes fused to a luciferase reporter gene, respond to GnRH with an increase in promoter activity comparable to that seen in primary rat pituitary cells. In this study, we have used this cell model to identify cis-acting elements of the LHß gene that mediate stimulation by GnRH. Analysis of a series of 5'-deletion and internal deletion constructs has revealed two regions of the rat LHß gene promoter involved in mediating the response to GnRH, region A (-490/-352) and region B (-207/-82). Fusion of region A upstream of a heterologous minimal promoter linked to the luciferase gene conferred GnRH responsiveness to the promoter, whereas region B did not. However, the presence of both regions A and B conferred a greater GnRH response than region A alone. Electrophoretic mobility shift assay revealed the presence of a protein(s) binding to region A using GH3 as well as {alpha}T3–1 nuclear extracts. Thus, region A (-490/-352) confers GnRH responsiveness to the LHß subunit gene and binds to a protein(s) present in pituitary cell lines. DNA sequences in region B (-207/-82) also contribute to GnRH responsiveness. The identification of putative GnRH response elements in the rat LHß gene promoter will aid in elucidation of the mechanisms of regulation of gene expression by GnRH.




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