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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
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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,
LHß, and FSHß (1). Recent studies have identified several
transcription factors that have profound effects on basal and/or
GnRH-stimulated LHß gene promoter activity.
Steroidogenic factor-1 (SF-1), a member of the nuclear hormone receptor
superfamily, is selectively expressed in the gonadotrope subpopulation
of the anterior pituitary gland, as well as in the adrenal gland and
the gonads (2). SF-1 binding elements have been identified in a range
of genes important for steroidogenesis, sexual differentiation, and
reproductive function (3). An SF-1 binding site was identified in the
glycoprotein -subunit gene (referred to as the gonadotrope-specific
element, or GSE) and SF-1 binding was shown to result in
transcriptional activation of this gene (4). Studies of the rat LHß
gene have identified and characterized two SF-1 binding elements,
located at positions -127 and -59 relative to the transcriptional
start site (Fig. 1
) (5, 6). The
functional role of SF-1 in trans-activation of the LHß
gene has been demonstrated in vivo and in vitro
(5, 6, 7, 8). However, the role of SF-1 in the regulation of GnRH
responsiveness of the LHß gene has not been fully characterized.
Pituitary SF-1 mRNA and protein levels have been reported by some
to increase in response to GnRH (9), whereas others have not observed
this regulation (10, 11, 12). SF-1 has been found to have no effect on the
fold activation of LHß gene promoter activity by GnRH (11, 13).
Transgenic mice null for the SF-1 gene have reduced levels of
gonadotropins, yet remain capable of responding to GnRH with an
increase in gonadotropin expression (2, 14). Thus, the role of SF-1 in
the regulation of LHß gene expression by GnRH remains
controversial.
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) (6, 16). Synergy between SF-1
and Egr-1 has been demonstrated in the activation of the LHß gene (6, 11, 12, 17). Transgenic mice null for Egr-1 demonstrated specific loss
of LHß gene expression and failed to respond to GnRH (16, 18). GnRH
is known to activate protein kinase C (PKC) in gonadotropes, and we
have demonstrated previously that activation of PKC increases
Egr-1 expression levels and also activates rat LHß gene
promoter activity, suggesting a role for Egr-1 in mediating the LHß
gene response to PKC (17, 19). Furthermore, GnRH increases Egr-1
expression in pituitary gonadotrope-derived cell lines, and mutations
of the Egr-1 binding sites almost completely prevent stimulation of the
proximal LHß gene promoter by GnRH, implicating Egr-1 as a critical
transcription factor involved in effecting this GnRH response (11, 12, 17, 20).
Our previous studies have identified additional DNA sequences further
upstream, between -490/-352, in the rat LHß gene promoter that are
also important for LHß gene expression and GnRH responsiveness
(13). More detailed analyses demonstrated several Sp1 binding sites
within this region (Fig. 1). Mutations of these elements, which block
binding of Sp1, reduce basal LHß gene promoter activity as well as
lessen the stimulation by GnRH (21, 22). Like Egr-1, Sp1 is
a member of the Cys2-His2
zinc finger family of transcription factors and recognizes a similar
but distinct GC-rich nucleotide sequence (23). These data suggest that
Sp1 also plays an important role in conferring GnRH responsiveness and
bring into question the requisite role of Egr-1 in this response.
The relative importance of these three transcription factors, Sp1, Egr-1, and SF-1, and possible interactions among them in mediating GnRH responsiveness have not been characterized. In this report, we demonstrate that all three transcription factors contribute to GnRH responsiveness and that the cognate binding sites form a tripartite GnRH response element. SF-1, while having little direct effect on GnRH responsiveness, has a critical role in integrating the effects of Sp1 and Egr-1 on the GnRH response.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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GGH3-1' cells (GH3 cells
stably transfected with rat GnRHR cDNA) were transfected with a
reporter construct containing region -797 to +5 of the rat LHß gene
promoter fused to a luciferase reporter (-797/+5LHßLUC) (Fig. 2). Treatment with a GnRH agonist
(GnRHAg) for 6 h increased luciferase activity 6.6 ±
0.4-fold, consistent with our previous reports. Cotransfection with the
cytomegalovirus (CMV)-driven SF-1 expression vector resulted in a
2.4 ± 0.1-fold increase in luciferase activity. Further
stimulation with GnRHAg in the presence of SF-1 resulted in a 5.7
± 0.2-fold stimulation in -797/+5LHßLUC activity (relative to
vehicle-treated cells expressing SF-1), statistically slightly
decreased from the fold GnRH response in the absence of SF-1
(P < 0.05). Cotransfection with the CMV-driven Egr-1
expression vector also increased luciferase activity by 6.5 ±
0.8-fold. Stimulation with GnRHAg in the presence of Egr-1 resulted in
a 4.4 ± 0.2-fold stimulation of luciferase activity, again
slightly decreased from the fold GnRH response in the absence of SF-1
and Egr-1 (P < 0.001). As previously reported, marked
synergy was observed in the presence of both SF-1 and Egr-1, with a
180 ± 17-fold increase. Interestingly, the fold response to GnRH
was almost completely abrogated (1.5 ± 0.1-fold) in the presence
of both Egr-1 and SF-1. The loss of GnRH responsiveness after
overexpression of both SF-1 and Egr-1 supports the possibility that
these factors may have critical roles in mediating the GnRH response.
If GnRH stimulates LHß gene expression by increasing levels of
functionally active SF-1 and Egr-1, then we would expect that no
further GnRH response could be elicited in the presence of high levels
of both SF-1 and Egr-1.
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). Therefore, these results do not
suggest a major contribution of the SF-1 and Egr-1 binding sites in the
rat LHß gene promoter in mediating GnRH responsiveness in
GGH3-1' cells.
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). Similar to our previous findings,
mutations in the Sp1 binding sites decreased the GnRH response
[7.1 ± 0.4-fold to 3.4 ± 0.2-fold (P <
0.001)]. Additional mutations in the SF-1 binding sites had no further
effect on the fold response to GnRH, but mutations in the Egr-1 binding
sites almost completely blocked GnRH responsiveness [2.0 ±
0.2-fold]. In sum, whereas blockade of Egr-1 binding had no effect on
GnRH response in the context of the wild-type LHß gene promoter
in GGH3-1' cells, mutations that prevent the
upstream binding of Sp1 "unmask" a role for Egr-1 in mediating GnRH
responsiveness.
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). In the presence of
SF-1, mutations in the Sp1, SF-1, or Egr-1 DNA binding elements
independently reduced GnRH responsiveness [-797/+5LHßLUC: 8.8
± 1.5-fold; LHSp1MLUC: 5.6 ± 0.8-fold; LHSF1MLUC: 5.2 ±
1.1-fold; LHEgr1MLUC: 4.1 ± 0.5-fold; LHSF1MEgr1MLUC:
5.4 ± 0.9-fold; P < 0.01 compared with
-797/+5LHßLUC]. In addition, combined mutations in the Sp1 and
either the SF-1 or Egr-1 binding elements almost completely abrogated
GnRH responsiveness [LHSp1MSF1MLUC: 2.6 ± 0.3-fold;
LHSp1MEgr1MLUC: 1.9 ± 0.2-fold;
LHSp1MSF1-MEgr1MLUC: 2.2 ± 0.1-fold]. In the
presence of SF-1, all three elements appear to contribute to mediate
the full GnRH response.
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- and ß- subunits of LH as well as GnRHR and SF-1 (24, 25).
LßT2 cells respond to pulsatile GnRH administration with an increase
in GnRHR and LHß mRNA levels (25). We have transfected LßT2 cells
with -797/+5LHßLUC by electroporation and demonstrated a 3.2 ±
0.2-fold increase in luciferase activity in response to GnRHAg (Fig. 6). In LßT2 cells, mutation of the Sp1
binding elements in the rat LHß gene decreased the fold response to
GnRH [2.3 ± 0.1-fold, P < 0.001]; mutation of
the SF-1 binding elements had no effect on the fold response to GnRH
[2.9 ± 0.3-fold, P = 0.4, NS]; and mutation
of the Egr-1 binding sites almost completely abolished stimulation of
the LHß gene promoter by GnRH [1.4 ± 0.1-fold]. Thus, as
anticipated from our results in GGH3-1' cells,
both the Sp1 and the Egr-1 binding elements appear to contribute to
mediating the full GnRH response in LßT2 cells (i.e. in
the presence of SF-1).
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A, -490/-353 deleted), one of the SF-1/Egr-1
composite elements (LHB, -207/-83 deleted), or the intervening 135
bp (LHC, -352/-208 deleted). These internal deletion constructs
were transfected into GGH3-1' cells, along with
either the SF-1 expression vector or the empty control vector (Fig. 7).
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A: 4.2 ± 0.2-fold, P
< 0.001; +SF-1: -797/+5LHßLUC: 7.8 ± 0.9-fold, LHA:
5.3 ± 0.2-fold, P < 0.005]. Internal deletion
of the SF-1 and Egr-1 binding sites resulted in a small but significant
decrease in the fold response to GnRH in the absence of SF-1, but a
more marked decrease in response to GnRH in the presence of SF-1
[-SF-1: LHB: 8.1 ± 0.6-fold, P < 0.001
compared with -797/+5LHßLUC; +SF-1: LHB: 1.6 ± 0.2-fold,
P < 0.001 compared with -797/+5LHßLUC], again
consistent with our observations using point mutations in these
elements (Figs. 3 and 5). Interestingly, internal deletion of the
intervening sequence (-359/-208) resulted in a decrease in the fold
response to GnRH, both in the absence and presence of SF-1, even though
all of the known binding sequences remain intact [-SF-1: LHC:
4.9 ± 0.3-fold, P < 0.001 compared with
-797/+5LHßLUC; +SF-1: LHC: 4.1 ± 0.4-fold,
P < 0.001 compared with -797/+5LHßLUC]. In
contrast, our previous studies have demonstrated that 5'-deletion of
this region has no effect on GnRH responsiveness (13). The
possibility that this deleted segment may contain transcriptionally
functional domains despite the lack of effect of 5'-deletion needs to
be considered. Nonetheless, these findings are consistent with the
hypothesis that the spacing between the Sp1 sites and the SF-1/Egr-1
sites is important for their interaction. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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SF-1 and Egr-1 were each able to transactivate the rat LHß gene
promoter but individually had little effect on the fold stimulation by
GnRH. In contrast, when both factors were present, basal LHß activity
was markedly and synergistically increased, and the response to GnRH
was almost completely abrogated (Fig. 2). Although squelching cannot be
ruled out, these results suggest that the GnRH stimulation of LHß
gene expression may be effected by increased levels of functionally
active SF-1 and Egr-1. To explore this observation further, we used the
approach of mutagenesis of the cognate binding sites.
Mutagenesis of the Egr-1 binding elements had no effect on the GnRH
response in GGH3-1' cells in the absence of SF-1
(Fig. 3). This was initially quite surprising in view of previous
reports. The Egr-1-/- mouse exhibits LHß
deficiency and fails to respond to gonadectomy with an increase in
LHß mRNA, suggesting a role for Egr-1 in mediating the
transcriptional regulation of the LHß gene by GnRH (16, 18). This
role was confirmed by in vitro studies (11, 12, 17, 20). In
these studies, mutations of the Egr-1 binding sites reduced or almost
completely abrogated GnRH responsiveness of the LHß gene promoter.
Closer evaluation reveals that the LHß promoter constructs used in
these studies did not include the upstream Sp1 binding sites.
Disruption of Sp1 binding to the LHß gene promoter, either by
mutation (Fig. 4), by internal deletion (Fig. 7), or by 5'-deletion (11, 12, 17, 20)
restores the importance of Egr-1 binding for the mediation of GnRH
responsiveness. These findings reconcile previous reports of the roles
of Sp1 and Egr-1 and indicate a novel functional relationship between
Sp1 and Egr-1 in mediating the GnRH response.
The role of SF-1 in the regulation of GnRH responsiveness of the LHß gene has been controversial. While SF-1-/- mice are deficient in LHß production (3), they remain responsive to GnRH with an increase in LHß levels (2, 14). In contrast, mutation of the SF-1 binding sites in the bovine LHß gene promoter prevented GnRH stimulation in transgenic mice (7). Using GGH3-1' cells that lack SF-1, we demonstrated previously that exogenous SF-1 increased both basal and GnRH-stimulated LHß gene promoter activity; however, the fold response to GnRH was unaffected (13). Interestingly, as shown here, in the presence of SF-1, both Egr-1 and Sp1 binding elements contribute to GnRH responsiveness, whereas only the Sp1 site appears important in the absence of SF-1. Thus, it appears that SF-1 plays an important indirect role by integrating the effects of Sp1 and Egr-1. One could speculate that levels of SF-1 in gonadotropes may modulate the relative roles in vivo of Sp1 and Egr-1 in mediating the GnRH response.
In LßT2 cells, mutation of the SF-1 sites somewhat surprisingly did
not affect the GnRH response (Fig. 6). The reason for this result is
not entirely clear. It may be due to differences in SF-1 levels between
GGH3-1' and LßT2 cells, other differences
between the two cell lines, or possibly due to the technical
limitations imposed by the comparatively small GnRH response observed
in LßT2 cells, making it more difficult to detect reductions in
responsiveness.
In the studies presented, we have not distinguished between the 5'
(-127/-106) and 3' (-59/-42) SF-1/Egr-1 composite elements. The
internal deletion studies in Fig. 7 indicate that the more 5'-site does
contribute to the GnRH response, but these studies do not
examine the 3' site in isolation. We have individually mutated
each of the SF-1 and Egr-1 binding sites and shown that each element
contributes to the overall GnRH response (data not shown). The 3' Egr-1
binding site appeared to have a slightly greater effect than the 5'
Egr-1 site, consistent with observations that the 3'-site has a higher
binding affinity for Egr-1 (L. Halvorson, unpublished data).
Our studies indicate that Sp1, SF-1, and Egr-1 act and interact to
contribute to GnRH responsiveness. Our results have led us to propose a
model in which these factors may interact with a common, as yet
unidentified, transcriptional cofactor (Fig. 8). According to our proposed model, Sp1,
when bound to its cognate elements in the LHß gene promoter, is able
to interact with this putative cofactor to mediate GnRH responsiveness.
The loss of Sp1 binding to the LHß gene promoter therefore results in
a decrease in the GnRH responsiveness of this gene. The decrease in
GnRH responsiveness observed upon deletion of intervening sequences
could be explained by disruption of interaction of Sp1 with the
putative cofactor caused by alterations in spacing.
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). As a result, mutation of the Egr-1 binding elements has no
effect on the GnRH response in the absence of SF-1 (Fig. 3). However,
if Sp1 binding is prevented, then the transcriptional cofactor is able
to interact with Egr-1 even in the absence of SF-1, enabling Egr-1 to
mediate GnRH responsiveness under these conditions (Fig. 4). We
postulate that the stoichiometry of the interaction is such that in the
absence of SF-1, the cofactor can interact with only Sp1 or Egr-1, but
not both, with a preferential interaction with Sp1 (Fig. 8). Such a
preferential interaction is not unprecedented. For example, NCoR
(nuclear receptor corepressor) preferentially binds to thyroid hormone
receptor when it is a homodimer rather than when it forms a heterodimer
with retinoid X receptor (26). In our model, Sp1, Egr-1, and SF-1 are shown interacting with a non-DNA-binding (classical) cofactor. These three transcription factors are known to interact variously with the coactivators SRC-1 and CBP/p300 (27, 28, 29, 30, 31), which were therefore tested for their role in mediating the GnRH response. In preliminary experiments in GGH3-1' and LßT2 cells, no effect on basal or GnRH-stimulated LHß gene promoter activity was observed with the addition of either cofactor (data not shown). While the interpretation of these experiments must be cautious, these results raise the intriguing possibility that a novel, possibly gonadotrope-specific or GnRH-regulated transcriptional coactivator may be involved. Efforts to identify such a factor are underway.
The cofactor depicted in the model could also be a transcription factor, binding directly to an as-yet- unidentified element in the LHß gene, or there may be more than one cofactor involved. Alternatively, it is possible that no cofactor is necessary, but rather Sp1, SF-1, and Egr-1 interact directly. Sp1 and SF-1 have been shown to interact directly to modulate CYP11A gene transcription (32), and direct protein-protein interaction between SF-1 and Egr-1 has also been reported (6, 11).
We have not yet addressed the role of Ptx1, a homeobox-containing transcription factor affecting the expression of multiple pituitary hormone genes, in the regulation of LHß gene expression (33). Ptx-1 has been shown to enhance LHß gene expression and to act in synergism with SF-1 and Egr-1 through direct protein-protein interaction in the stimulation of LHß gene expression (11). The role of Ptx-1 in GnRH responsiveness remains to be studied.
Physiologically, all three of these transcription factors are present in gonadotropes and are likely to interact to mediate the response to GnRH. Therefore, the cognate binding sites for these factors can be considered to form a tripartite GnRH response element. It is possible that such a composite GnRH response element provides a level of redundancy to protect such a critical point of regulation of reproductive function.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Reporter Plasmids and Expression Vectors
The wild-type reporter construct used for these studies
contained 797 bp of the 5'-flanking sequence of the rat LHß gene and
the first 5 bp of the 5'-untranslated region, cloned into the pXP2
luciferase reporter vector (-797/+5LHßLUC) (34, 35). The
Transformer site-directed mutagenesis kit (CLONTECH Laboratories, Inc., Palo Alto, CA) was used to introduce point mutations into
the Sp1, SF-1, and Egr-1 binding sites in -797/+5LHßLUC.
Oligonucleotides used have been described previously (17, 21) and are
summarized in Table 1. Generation of
multiple mutations was performed either simultaneously or sequentially
and required the use of two selection primers (mpXP2 and mpXP2Rev), as
described previously (17). All mutagenic constructs were confirmed by
dideoxysequencing.
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A
(-490/-353 deleted) and LHB (-207/-83 deleted) were generated as
previously reported (13). Additional primers, LHß56S
(5'-GTGTTTAAAGCAAATTTGAGCCAATGTCAGTTAAGCTCAG-3') and LHß65AS
(5'-CTGAGCTTAACTGACATTGGCTCAAATTTGCTTTAAACAC-3'), were used to generate
LHC (-359/-208 deleted). All constructs were confirmed by
dideoxysequencing. The SF-1 expression vector contained 2.1 kb of the murine SF-1 cDNA driven by CMV promoter sequences in the vector, pCMV5 (kindly provided by K. L. Parker, Southwestern School of Medicine, Dallas, TX) (36). The Egr-1 expression vector was generated by cloning the murine Egr-1 cDNA (provided by D. Nathans, John Hopkins University, Baltimore, MD) (37) into pCMV5 at BamHI and HindIII restriction enzyme sites. The F-SRC-1 expression vector, encoding the full-length human SRC-1 cDNA in pcDNA1/Amp, was generously provided by Dr. Akira Takeshita (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA) (38). An expression vector containing p300 cDNA under the control of CMV promoter sequences was the generous gift of Dr. D. M. Livingston (Dana Farber Cancer Institute, Harvard Medical School, Boston, MA) (39). An expression vector expressing ß-galactosidase driven by the Rous sarcoma virus promoter (RSV-ß-Gal) was used as an internal standard and control (40).
Cell Culture and Transfection
GGH3-1' cells were prepared by stably
transfecting GH3 cells with the rat GnRHR cDNA,
as described previously (41). LßT2 cells were generously provided by
Dr. P. L. Mellon (University of California, San Diego, CA) (24, 25). GGH3-1' and LßT2 cells were maintained in
monolayer culture in DMEM (GGH3-1' cells in low
glucose media and LßT2 cells in high glucose media) supplemented with
10% (vol/vol) FBS at 37 C in humidified 5%
CO2/95% air. For transient transfection studies,
cells were cultured to 50–70% confluence and transfected by
electroporation. In each experiment, approximately 5 x
106 cells were suspended in 0.4 ml of Dulbecco’s
PBS plus 5 mM glucose containing the DNA to be transfected.
The cells received a single electrical pulse of 240 V from a total
capacitance of 1000 microfarads, using an Electroporator II apparatus
(Invitrogen, San Diego, CA). Cells received 2 µg/well of
the reporter constructs. Where appropriate, cells also received 1
µg/well of SF-1, Egr-1, F-SRC-1, and/or p300 expression vectors or an
equivalent amount of the empty pCMV5 expression vector. Cells were
cotransfected with RSV-ß-Gal (1 µg/well). After electroporation,
cells were plated in serum-containing medium. Medium was replaced after
24 h, and cells were harvested 48 h after transfection. Cells
were treated with 100 nM GnRHAg or vehicle for 6 h
immediately before harvesting. Cell extracts were prepared and analyzed
for luciferase and ß-galactosidase activities as described previously
(40, 42). Luciferase activity was normalized to the level of
ß-galactosidase activity. Data are shown as mean ±
SEM.
Statistical Analysis
Transfections were performed in triplicate and repeated at least
three times. Data were combined across transfection experiments to
determine the mean ± SEM of the corrected luciferase
activity for basal and GnRHAg-treated cells, and fold stimulation in
response to GnRH was calculated. Two-way ANOVA followed by post hoc
comparisons with Fisher’s protected least significant difference test
was used to assess whether changes in GnRH responsiveness were
statistically significant between the indicated groups. Significant
differences were established as P < 0.05.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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This work was supported in part by NIH Grants R29-HD-33001 and R01-HD-19938 (U.B.K.) and R01-HD-38089 and R03-HD-34692 (L.M.H.) and by the George W. Thorn Center (U.B.K.).
Received for publication December 13, 1999. Revision received April 25, 2000. Accepted for publication May 1, 2000.
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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M. A. Lawson, R. Tsutsumi, H. Zhang, I. Talukdar, B. K. Butler, S. J. Santos, P. L. Mellon, and N. J. G. Webster Pulse Sensitivity of the Luteinizing Hormone {beta} Promoter Is Determined by a Negative Feedback Loop Involving Early Growth Response-1 and Ngfi-A Binding Protein 1 and 2 Mol. Endocrinol., May 1, 2007; 21(5): 1175 - 1191. [Abstract] [Full Text] [PDF]
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S. Maudsley, Z. Naor, D. Bonfil, L. Davidson, D. Karali, A. J. Pawson, R. Larder, C. Pope, N. Nelson, R. P. Millar, et al. Proline-Rich Tyrosine Kinase 2 Mediates Gonadotropin-Releasing Hormone Signaling to a Specific Extracellularly Regulated Kinase-Sensitive Transcriptional Locus in the Luteinizing Hormone {beta}-Subunit Gene Mol. Endocrinol., May 1, 2007; 21(5): 1216 - 1233. [Abstract] [Full Text] [PDF]
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T. B. Salisbury, A. K. Binder, J. C. Grammer, and J. H. Nilson Maximal Activity of the Luteinizing Hormone{beta}-Subunit Gene Requires {beta}-Catenin Mol. Endocrinol., April 1, 2007; 21(4): 963 - 971. [Abstract] [Full Text] [PDF]
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 W. Zheng, J. Yang, Q. Jiang, Z. He, and L. M Halvorson Liver receptor homologue-1 regulates gonadotrope function J. Mol. Endocrinol., February 1, 2007; 38(2): 207 - 219. [Abstract] [Full Text] [PDF]
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H. Zhang, J. S. Bailey, D. Coss, B. Lin, R. Tsutsumi, M. A. Lawson, P. L. Mellon, and N. J. G. Webster Activin Modulates the Transcriptional Response of LssT2 Cells to Gonadotropin-Releasing Hormone and Alters Cellular Proliferation Mol. Endocrinol., November 1, 2006; 20(11): 2909 - 2930. [Abstract] [Full Text] [PDF]
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 F. Ruf, M.-J. Park, F. Hayot, G. Lin, B. Roysam, Y. Ge, and S. C. Sealfon Mixed Analog/Digital Gonadotrope Biosynthetic Response to Gonadotropin-releasing Hormone J. Biol. Chem., October 13, 2006; 281(41): 30967 - 30978. [Abstract] [Full Text] [PDF]
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K. Sayasith, K. A Brown, J. G Lussier, M. Dore, and J. Sirois Characterization of bovine early growth response factor-1 and its gonadotropin-dependent regulation in ovarian follicles prior to ovulation. J. Mol. Endocrinol., October 1, 2006; 37(2): 239 - 250. [Abstract] [Full Text] [PDF]
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H. A. Ferris and M. A. Shupnik Mechanisms for Pulsatile Regulation of the Gonadotropin Subunit Genes by GNRH1 Biol Reprod, June 1, 2006; 74(6): 993 - 998. [Abstract] [Full Text] [PDF]
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H. Kanasaki, G. Y. Bedecarrats, K.-Y. Kam, S. Xu, and U. B. Kaiser Gonadotropin-Releasing Hormone Pulse Frequency-Dependent Activation of Extracellular Signal-Regulated Kinase Pathways in Perifused L{beta}T2 Cells Endocrinology, December 1, 2005; 146(12): 5503 - 5513. [Abstract] [Full Text] [PDF]
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N. J. Westphal and A. F. Seasholtz Gonadotropin-Releasing Hormone (GnRH) Positively Regulates Corticotropin-Releasing Hormone-Binding Protein Expression via Multiple Intracellular Signaling Pathways and a Multipartite GnRH Response Element in {alpha}T3-1 Cells Mol. Endocrinol., November 1, 2005; 19(11): 2780 - 2797. [Abstract] [Full Text] [PDF]
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Q. Jiang, K.-H. Jeong, C. D Horton, and L. M Halvorson Pituitary homeobox 1 (Pitx1) stimulates rat LH{beta} gene expression via two functional DNA-regulatory regions J. Mol. Endocrinol., August 1, 2005; 35(1): 145 - 158. [Abstract] [Full Text] [PDF]
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M. J. Wilson, P. Jeyasuria, K. L. Parker, and P. Koopman The Transcription Factors Steroidogenic Factor-1 and SOX9 Regulate Expression of Vanin-1 during Mouse Testis Development J. Biol. Chem., February 18, 2005; 280(7): 5917 - 5923. [Abstract] [Full Text] [PDF]
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L L Burger, D J Haisenleder, A C Dalkin, and J C Marshall Regulation of gonadotropin subunit gene transcription J. Mol. Endocrinol., December 1, 2004; 33(3): 559 - 584. [Abstract] [Full Text] [PDF]
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B. E. West, G. E. Parker, J. J. Savage, P. Kiratipranon, K. S. Toomey, L. R. Beach, S. C. Colvin, K. W. Sloop, and S. J. Rhodes Regulation of the Follicle-Stimulating Hormone {beta} Gene by the LHX3 LIM-Homeodomain Transcription Factor Endocrinology, November 1, 2004; 145(11): 4866 - 4879. [Abstract] [Full Text] [PDF]
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 J. S. Jorgensen, C. C. Quirk, and J. H. Nilson Multiple and Overlapping Combinatorial Codes Orchestrate Hormonal Responsiveness and Dictate Cell-Specific Expression of the Genes Encoding Luteinizing Hormone Endocr. Rev., August 1, 2004; 25(4): 521 - 542. [Abstract] [Full Text] [PDF]
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D. Curtin, H. A. Ferris, M. Hakli, M. Gibson, O. A. Janne, J. J. Palvimo, and M. A. Shupnik Small Nuclear RING Finger Protein Stimulates the Rat Luteinizing Hormone-{beta} Promoter by Interacting with Sp1 and Steroidogenic Factor-1 and Protects from Androgen Suppression Mol. Endocrinol., May 1, 2004; 18(5): 1263 - 1276. [Abstract] [Full Text] [PDF]
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D. J. Bernard Both SMAD2 and SMAD3 Mediate Activin-Stimulated Expression of the Follicle-Stimulating Hormone {beta} Subunit in Mouse Gonadotrope Cells Mol. Endocrinol., March 1, 2004; 18(3): 606 - 623. [Abstract] [Full Text] [PDF]
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J.-F. Mouillet, C. Sonnenberg-Hirche, X. Yan, and Y. Sadovsky p300 Regulates the Synergy of Steroidogenic Factor-1 and Early Growth Response-1 in Activating Luteinizing Hormone-{beta} Subunit Gene J. Biol. Chem., February 27, 2004; 279(9): 7832 - 7839. [Abstract] [Full Text] [PDF]
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L. K. Bachir, G. Garrel, A. Lozach, J.-N. Laverriere, and R. Counis The Rat Pituitary Promoter of the Neuronal Nitric Oxide Synthase Gene Contains an Sp1-, LIM Homeodomain-Dependent Enhancer and a Distinct Bipartite Gonadotropin-Releasing Hormone-Responsive Region Endocrinology, September 1, 2003; 144(9): 3995 - 4007. [Abstract] [Full Text] [PDF]
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A. K. Ghosh, R. Steele, and R. B. Ray Modulation of Human Luteinizing Hormone {beta} Gene Transcription by MIP-2A J. Biol. Chem., June 20, 2003; 278(26): 24033 - 24038. [Abstract] [Full Text] [PDF]
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D. J. Haisenleder, H. A. Ferris, and M. A. Shupnik The Calcium Component of Gonadotropin-Releasing Hormone-Stimulated Luteinizing Hormone Subunit Gene Transcription Is Mediated by Calcium/Calmodulin-Dependent Protein Kinase Type II Endocrinology, June 1, 2003; 144(6): 2409 - 2416. [Abstract] [Full Text] [PDF]
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G. Y. Bedecarrats and U. B. Kaiser Differential Regulation of Gonadotropin Subunit Gene Promoter Activity by Pulsatile Gonadotropin-Releasing Hormone (GnRH) in Perifused L{beta}T2 Cells: Role of GnRH Receptor Concentration Endocrinology, May 1, 2003; 144(5): 1802 - 1811. [Abstract] [Full Text] [PDF]
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C. C. Quirk, D. D. Seachrist, and J. H. Nilson Embryonic Expression of the Luteinizing Hormone beta Gene Appears to Be Coupled to the Transient Appearance of p8, a High Mobility Group-related Transcription Factor J. Biol. Chem., January 10, 2003; 278(3): 1680 - 1685. [Abstract] [Full Text] [PDF]
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V. V. Vasilyev, M. A. Lawson, D. Dipaolo, N. J. G. Webster, and P. L. Mellon Different Signaling Pathways Control Acute Induction versus Long-Term Repression of LH{beta} Transcription by GnRH Endocrinology, September 1, 2002; 143(9): 3414 - 3426. [Abstract] [Full Text] [PDF]
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P. Melamed, M. Koh, P. Preklathan, L. Bei, and C. Hew Multiple Mechanisms for Pitx-1 Transactivation of a Luteinizing Hormone beta Subunit Gene J. Biol. Chem., July 12, 2002; 277(29): 26200 - 26207. [Abstract] [Full Text] [PDF]
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 J. E. Dumont, S. Dremier, I. Pirson, and C. Maenhaut Cross signaling, cell specificity, and physiology Am J Physiol Cell Physiol, July 1, 2002; 283(1): C2 - C28. [Abstract] [Full Text] [PDF]
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S. B. Rosenberg and P. L. Mellon An Otx-Related Homeodomain Protein Binds an LH{beta} Promoter Element Important for Activation During Gonadotrope Maturation Mol. Endocrinol., June 1, 2002; 16(6): 1280 - 1298. [Abstract] [Full Text] [PDF]
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W. W. Woodmansee, R. L. Mouser, D. F. Gordon, J. M. Dowding, W. M. Wood, and E. C. Ridgway Mutational Analysis of the Mouse Somatostatin Receptor Type 5 Gene Promoter Endocrinology, June 1, 2002; 143(6): 2268 - 2276. [Abstract] [Full Text] [PDF]
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E. Wurmbach, T. Yuen, B. J. Ebersole, and S. C. Sealfon Gonadotropin-releasing Hormone Receptor-coupled Gene Network Organization J. Biol. Chem., December 7, 2001; 276(50): 47195 - 47201. [Abstract] [Full Text] [PDF]
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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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