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Endocrine-Hypertension Division (U.B.K.) and Genetics Division
(M.T.C.) Department of Medicine Brigham and Women’s Hospital
and Harvard Medical School Boston, Massachusetts 02115
Department of Obstetrics and Gynecology (L.M.H.) New England
Medical Center Tufts University School of Medicine Boston,
Massachusetts 02111
Recently, several cis-regulatory elements that play roles in LHß gene expression, and their cognate DNA-binding transcription factors, have been identified. These factors include Sp1, steroidogenic factor-1 (SF-1), and early growth response protein 1 (Egr-1). Using the GH3 pituitary cell line (which lacks SF-1) as a model, we demonstrate that expression of SF-1 or Egr-1 increases rat LHß gene promoter activity but has little effect on the fold response to GnRH. However, expression of both SF-1 and Egr-1 synergistically enhances LHß gene promoter activity and prevents further stimulation of activity by GnRH. Mutations in the Sp1 binding sites of the rat LHß gene promoter decrease GnRH responsiveness, whereas mutations in the SF-1 and/or Egr-1 binding sites alone have little effect on the GnRH response. Combinatorial mutations in both the Sp1 and Egr-1 binding elements result in almost complete loss of the GnRH response. In contrast, in GH3 cells cotransfected with SF-1, mutations in the Sp1, SF-1, or Egr-1 binding elements independently decrease GnRH responsiveness. In LßT2 cells, a gonadotrope-derived cell line that expresses SF-1 endogenously, mutations in either the Sp1 or Egr-1 binding elements decrease GnRH responsiveness. These data suggest that the Sp1, SF-1, and Egr-1 binding sites form a tripartite GnRH response element in the rat LHß gene promoter. Changes in the spacing between the upstream Sp1 binding sites and the downstream SF-1/Egr-1 binding elements reduce the response to GnRH. SF-1, while having little direct effect on GnRH responsiveness, has a critical role in integrating the effects of Sp1 and Egr-1.
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D. Curtin, S. Jenkins, N. Farmer, A. C. Anderson, D. J. Haisenleder, E. Rissman, E. M. Wilson, and M. A. Shupnik Androgen Suppression of GnRH-Stimulated Rat LH{beta} Gene Transcription Occurs Through Sp1 Sites in the Distal GnRH-Responsive Promoter Region Mol. Endocrinol., November 1, 2001; 15(11): 1906 - 1917. [Abstract] [Full Text] [PDF]
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L. Guillemot, A. Levy, M. Raymondjean, and B. Rothhut Angiotensin II-induced Transcriptional Activation of the Cyclin D1 Gene Is Mediated by Egr-1 in CHO-AT1A Cells J. Biol. Chem., October 12, 2001; 276(42): 39394 - 39403. [Abstract] [Full Text] [PDF]
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J. S. Jorgensen and J. H. Nilson AR Suppresses Transcription of the LH{beta} Subunit by Interacting with Steroidogenic Factor-1 Mol. Endocrinol., September 1, 2001; 15(9): 1505 - 1516. [Abstract] [Full Text] [PDF]
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C. C. Quirk, K. L. Lozada, R. A. Keri, and J. H. Nilson A Single Pitx1 Binding Site Is Essential for Activity of the LH{beta} Promoter in Transgenic Mice Mol. Endocrinol., May 1, 2001; 15(5): 734 - 746. [Abstract] [Full Text]
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J. J. Tremblay and R. S. Viger Nuclear Receptor Dax-1 Represses the Transcriptional Cooperation Between GATA-4 and SF-1 in Sertoli Cells Biol Reprod, April 1, 2001; 64(4): 1191 - 1199. [Abstract] [Full Text]
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