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Molecular Endocrinology 14 (4): 472-485
Copyright © 2000 by The Endocrine Society

Divergent and Composite Gonadotropin-Releasing Hormone-Responsive Elements in the Rat Luteinizing Hormone Subunit Genes

Jennifer Weck1, Alice C. Anderson, Shannon Jenkins, Patricia C. Fallest and Margaret A. Shupnik

Division of Endocrinology Department of Internal Medicine (A.C.A., S.J., P.C.F., M.A.S.) Department of Molecular Physiology and Biological Physics (J.W., M.A.S.), and The National Science Foundation Center for Biological Timing University of Virginia Charlottesville, Virginia 22903

GnRH pulses regulate gonadotropin subunit gene transcription in a frequency-dependent, subunit-specific manner. The {alpha}-subunit gene is stimulated by constant GnRH and by rapid to intermediate pulse frequencies, while stimulation of LHß subunit gene transcription requires intermediate frequency pulses. We have defined the GnRH-responsive elements of the rat LH subunit gene promoters by deletion/mutation analysis and transfection studies in rat pituitary cells and two clonal gonadotrope cell lines. The {alpha}-subunit gene GnRH-responsive region lies between -411 and -375 bp. The region contains two Ets-domain protein binding sites, and mutating either site obliterates the response. DNA protein binding studies demonstrate the two sites are not equivalent, and that Ets-1 does not mediate this response. Studies of the LHß promoter reveal a major GnRH-responsive region between -456 and -342 bp. Within this region, two Sp1 binding sites contribute to the GnRH response, and the 3'Sp1 site is also critical for basal expression. The 5'Sp1 site partially overlaps a CArG box, and mutating the CArG element specifically eliminates the response to pulsatile GnRH. DNA containing this mutation cannot form intermediate mobility complexes with nuclear proteins, but retains Sp1 binding. Mutation of the 3'Sp1 site and either the 5'Sp1 or CArG element partially restores GnRH stimulation, suggesting a downstream element contributes to the full GnRH response. These studies demonstrate that unique composite elements and transcription factors are responsible for GnRH stimulation of the LH subunit genes and may contribute to their differential responses to GnRH pulses.




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