Activation of Luteinizing Hormone β Gene by Gonadotropin-releasing Hormone Requires the Synergy of Early Growth Response-1 and Steroidogenic Factor-1*
- From the ‡Department of Obstetrics and Gynecology, the§Department of Pathology, and the ¶Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110
Abstract
We have previously shown that early growth response (Egr) 1-deficient mice exhibit female infertility, reflecting a luteinizing hormone (LH) β deficiency. Egr-1 activates the LHβ gene in vitro through synergy with steroidogenic factor-1 (SF-1), a protein required for gonadotrope function. To test if this synergy is essential for gonadotropin-releasing hormone (GnRH) stimulation of LHβ, we examined the activity of the LHβ promoter in the gonadotrope cell line LβT2. GnRH markedly stimulated the LHβ promoter (15-fold). Mutation of either Egr-1 or SF-1 elements within the LHβ promoter attenuated this stimulation, whereas mutation of both promoter elements abrogated GnRH induction of the LHβ promoter. Furthermore, GnRH stimulated Egr-1 but not SF-1 expression in LβT2 cells. Importantly, overexpression of Egr-1 alone was sufficient to enhance LHβ expression. Although other Egr proteins are expressed in LβT2 cells and are capable of interacting with SF-1, GnRH stimulation of Egr-1 was the most robust. We also found that the nuclear receptor DAX-1, a repressor of SF-1 activity, reduced Egr-1–SF-1 synergy and diminished GnRH stimulation of the LHβ promoter. We conclude that the synergy between Egr-1 and SF-1 is essential for GnRH stimulation of the LHβ gene and plays a central role in the dynamic regulation of LHβ expression.
Footnotes
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↵* This work was supported by Deutsche Forschungsgemeinschaft Grant DO-653/1 (to C. D.), National Institutes of Health Grant HD-34110, and the Howard Hughes Medical Institute Pilot Research Projects Award (to Y. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‖ To whom correspondence should be addressed: Dept. of Obstetrics and Gynecology, Washington University School of Medicine, P. O. Box 8064, 4911 Barnes-Jewish Hospital Plaza, St. Louis, MO 63110. Tel.: 314-747-0937; Fax: 314-362-8580; E-mail:sadovskyy{at}msnotes.wustl.edu.
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↵2 J. Svaren, manuscript in preparation.
- Abbreviations:
- GnRH
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gonadotropin-releasing hormone
- LH
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luteinizing hormone
- Egr
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early growth response
- SF-1
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steroidogenic factor-1
- DAX-1
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dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on chromosome X, gene 1
- PCR
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polymerase chain reaction
- CMV
-
cytomegalovirus
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- Received November 20, 1998.
- Revision received February 16, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
