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Division of Endocrinology, Metabolism, and Molecular Medicine (W.R.D., M.I., Y.P., J.L.J.), Cell and Molecular Biology (E.T.M., M.H.D.), Northwestern University Medical School, Chicago, Illinois 60611
Address all correspondence and requests for reprints to: J. Larry Jameson, M.D., Ph.D., Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Tarry 15-709, 303 East Chicago Avenue, Chicago, Illinois 60611-3008. E-mail: ljameson{at}northwestern.edu
Pulsatile secretion of GnRH is the major regulator of
gonadotropin (LH, FSH) gene expression and secretion. Recently, GnRH
has been shown to rapidly stimulate the expression of early growth
response protein-1 (Egr-1), a transcription factor that is essential
for LHß gene expression in the pituitary. In this study, we examined
the regulatory elements and signal transduction pathways by which GnRH
regulates Egr-1 transcription. Deletion analysis of the murine Egr-1
promoter identified two regions (-370 to -342 and -116 to -73) that
are critical for GnRH responsiveness in 
T3 pituitary gonadotrope
cells. The first region, which contains two serum response elements
(SREs), contributed about 70–80% of GnRH inducibility, whereas the
second region, which contains two SREs and one Ets binding site,
conferred an additional 20–30% of activity. Mutations that
abolish protein binding to these SREs and Ets binding sites completely
eliminated GnRH-mediated transcriptional activation of the Egr-1
promoter. Mutation of cAMP response element reduced promoter activity
by 40%. Using specific protein kinase inhibitors, GnRH stimulation of
Egr-1 expression was found to be dependent on PKC/ERK pathways. In
addition, GnRH activated p90 ribosomal S6 kinase, which has the
potential to phosphorylate serum response factor and cAMP response
element binding protein. We conclude that GnRH stimulation of Egr-1
gene expression requires several distinct SREs/Ets elements and a cAMP
response element and is mediated via activation of PKC/ERK
signaling pathways.
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