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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: 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
The regulation of LH and FSH subunit gene expression is under the
control of GnRH. Physiological changes in the frequency of pulsatile
GnRH release from the hypothalamus result in differential stimulation
of 
-, LHß-, and FSHß-gene expression. Previous studies indicate
that the GnRH receptor couples to G proteins of the Gq/11
family, with phosphoinositide turnover and its resultant increase in
intracellular calcium concentration and protein kinase C (PKC)
activation, to stimulate secretion of LH and FSH. However, the
molecular mechanisms by which GnRH mediates its transcriptional effects
remain largely unknown. We used GH3 cells, constitutively
expressing the rat GnRH receptor (GGH3-1' cells) and
transiently transfected with a luciferase reporter gene controlled by
either the , LHß, or FSHß gene regulatory region (LUC,
LHßLUC, and FSHßLUC, respectively), to examine the roles of several
signal transduction pathways in the GnRH-mediated stimulation of
gonadotropin subunit gene expression. Activation of PKC by phorbol,
12-myristate, 13-acetate resulted in an increase in the luciferase
activity of all three gonadotropin subunit gene reporter constructs.
Phorbol, 12-myristate, 13-acetate had a greater stimulatory effect,
relative to the maximal stimulation with GnRH, for the ß-subunit
genes than for the -subunit gene. Depletion of PKC, or inhibition of
PKC by GF109203X, demonstrated that PKC-dependent pathways play a
larger role in the GnRH-mediated transcriptional control of the LHß-
and FSHß-genes than the -subunit gene. In contrast, an L-type
calcium channel agonist, Bay K 8644, was able to stimulate LUC but
not LHßLUC or FSHßLUC. Nimodipine, an L-type calcium channel
antagonist, had a larger inhibitory effect on the GnRH response of
LUC, relative to LHßLUC or FSHßLUC. We conclude from these
results that the differential regulation of gonadotropin subunit gene
expression by GnRH is caused, in part, by differential use of signal
transduction pathways, activated upon GnRH binding.
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L. M. Halvorson, U. B. Kaiser, and W. W. Chin The Protein Kinase C System Acts through the Early Growth Response Protein 1 to Increase LH{beta} Gene Expression in Synergy with Steroidogenic Factor-1 Mol. Endocrinol., January 1, 1999; 13(1): 106 - 116. [Abstract] [Full Text]
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