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-Subunit Gene by Androgen Receptor Occurs Independently of DNA Binding but Requires the DNA-Binding and Ligand-Binding Domains of the Receptor
Department of Molecular and Integrative Physiology (L.L.H.), The
University of Kansas Medical Center, Kansas City, Kansas 66160,
The Laboratories for Reproductive Biology (E.M.W.), The
University of North Carolina, Chapel Hill, North Carolina
27599-7500,
Department of Pharmacology (J.H.N.), School of
Medicine, Case Western Reserve University, Cleveland, Ohio
44106
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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-subunit shared by these hormones is
transcriptionally repressed by androgen receptor (AR) in the presence
of its ligand dihydrotestosterone. This identifies at least one
mechanism that contributes to AR-dependent suppression of gonadotropin
synthesis. Repression of -subunit transcription by AR requires only
the sequences within the first 480 bp of the promoter. While this
region contains a high-affinity binding site for AR, this element does
not mediate the suppressive effects of androgens. Instead, two
other elements within the promoter-regulatory region (-basal element
and cAMP-regulatory element), which are important for expression of the
-subunit gene in gonadotropes, mediate the effects of AR. This
suggests that AR inhibits activity of the -subunit promoter by
interfering with the transcriptional properties of the proteins that
bind to -basal element and the cAMP-regulatory elements.
Furthermore, transfection analysis of various mutant ARs identified
both the DNA-binding and ligand-binding domains of the receptor as
critical for repression. Comparisons with the MMTV promoter revealed
distinct structural requirements that underlie the transactivation and
transrepression properties of AR. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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-subunit (1). This
subunit dimerizes with unique ß-subunits to generate LH, FSH, TSH,
and chorionic gonadotropin (CG) (1). This family of heterodimeric
glycoproteins are critical regulators of reproduction and metabolism.
Since the -subunit is required for the production of all
glycoprotein hormones, its expression must occur in each population of
cells that produce these hormones. Thus, the -subunit gene is
expressed in the gonadotropes (LH and FSH) and thyrotropes (TSH) of the
pituitary and in the trophoblast cells of the placenta (CG).
Regulation of this gene in gonadotropes involves input from both the
hypothalamus and the gonads (2). The hypothalamic neuropeptide GnRH
stimulates synthesis and secretion of gonadotropins by binding a
specific G protein- coupled receptor on the surface of gonadotropes (2, 3). This increase in synthesis and secretion is accompanied by changes
in transcription of the -subunit gene (7, 8). This gene is also
regulated through feedback signals from the gonads (2, 4, 5, 6).
Typically, estrogens and androgens synthesized in response to
gonadotropin stimulation repress transcription of the - and
gonadotropin ß-subunit genes (4, 5, 6, 9, 10, 11, 12). Mechanistically, negative
feedback by gonadal steroids may reflect either direct regulatory
effects occurring at the level of the pituitary or an indirect
mechanism involving inhibition of GnRH synthesis and secretion from
hypothalamic neurons (4, 5, 6). Several lines of evidence, however,
suggest that direct transcriptional regulation of the - subunit gene
by androgens occurs within the pituitary and constitutes an important
component of negative feedback (9, 11, 13, 14, 15, 16).
Unlike negative regulation by glucocorticoid receptor, which
predominantly exerts its negative regulatory effects by interacting
with the transcription factor AP-1, the mechanism by which AR
negatively influences transcription is less well understood. In one of
the first reports on negative regulation by AR, we demonstrated that
transcription of the -subunit gene was repressed by androgens when
promoter constructs, together with AR, were introduced into a
gonadotrope cell line, T3 (9). Repression was dependent on both the
presence of AR and its ligand, dihydrotestosterone (DHT). This study
also identified a high-affinity binding site for androgen receptor
(ARE) located between the tandem CREs and the CCAAT box in the proximal
promoter region of the -subunit gene (Fig. 1
) (9). This site mapped to a previously
identified promoter element, the junctional response element or JRE,
which is important for expression in the placenta and has significant
sequence identity to an ARE/glucocorticoid response element consensus
site (9). Based on these studies, we postulated that direct binding of
activated AR to the JRE represses transcription of the -subunit
gene, accounting, at least partially, for the physiological regulation
of the -subunit by androgens. In the present study, however, we show
instead that AR represses promoter activity via a mechanism that does
not require a high-affinity binding site for the steroid receptor.
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-subunit gene in gonadotropes is complex, involving an array of
regulatory elements located between -330 and -95 bp of the
5'-flanking region (17, 18, 19). These include two tandem cAMP-regulatory
elements (CREs), a GATA-binding site within the upstream regulatory
element (URE), the gonadotrope-specific element (GSE), the pituitary
glycoprotein hormone basal element (PGBE), and -basal element
(BE) (Fig. 1
) (17, 18, 19). A CCAAT box also contributes minimally to
promoter activity (our unpublished data). Using mutations within these
important elements, we report herein that repression occurs via a
mechanism requiring the presence of two promoter elements, BE and
the tandem CREs. Mediation of androgen suppression by these two
elements suggests that AR interferes with the transcriptional
properties of the proteins that bind them. Furthermore, our studies
identify regions within the DNA-binding domain (DBD) and the
ligand-binding domain (LBD) of AR that are critical for repression and
demonstrate that there are distinct receptor structural requirements
for mechanisms of activation and repression by AR. |
RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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-subunit promoters. Promoter constructs were introduced into T3
cells along with expression vectors for either AR (pCMVhAR) or GH
(CMV-GH). Cotransfection of CMV-GH was included to control for changes
in -subunit promoter activity due to the cotransfection paradigm.
Both AR and GH are expressed from the cytomegalovirus (CMV) promoter.
Cells were then maintained in media containing 100 nM DHT.
In the presence of pCMVhAR, activity of the wild type -1500 bp
promoter (-1500 wt) was repressed approximately 2-fold when compared
with the CMV-GH control (Fig. 2A). A
mutation through the ARE (µARE, see Fig. 1) did not affect that
ability of the receptor to repress promoter activity (Fig. 2A).
Furthermore, deletion of promoter sequences upstream of -485 did not
diminish AR regulation, demonstrating that the -485 bp
promoter-proximal region mediates the suppressive effect of AR.
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-subunit promoter was confirmed by
electrophoretic mobility shift analysis (Fig. 2B). A promoter fragment
spanning -485 to +45bp was radiolabeled and incubated with purified
DBD of the rat AR (AR-DBD) and an antibody specific for AR (AR52). In
the presence of AR-DBD and AR52, a single major complex bound to the
wild type promoter (-485 wt). This band was eliminated when excess
unlabeled -subunit ARE competitor was added to the reaction. No AR
complex was formed on the promoter containing a mutation through the
ARE (-485 µARE).
The above data demonstrate that androgen-dependent suppression occurs
in the absence of a high-affinity binding site for AR. This suggested
that AR interferes with the activity of a transcription factor(s)
required for promoter activity either by binding directly to the factor
or indirectly by competing for a common transcriptional adapter. Thus,
to examine this possibility further, we elected to determine whether
repression by AR mapped to other regulatory elements within the
-subunit promoter.
Repression by AR Requires Basal Promoter Elements Important for
Expression of the -Subunit in Gonadotropes
To identify regulatory elements required for AR repression, we
took advantage of numerous studies from this laboratory and others that
have elucidated a complex array of elements required for activity of
the -subunit promoter in gonadotropes (Fig. 1) (17, 18, 19). In short,
we examined the effects of AR on a series of promoter constructs
containing block replacement mutations through each of these elements.
Details of the mutations are explained elsewhere (19). As shown in Fig. 3, promoter constructs containing
mutations through the PGBE (
PGBE), GSE (GSE), or the URE (URE)
were all repressed by AR, although to a slightly lesser degree than the
wild type promoter. In contrast, promoters containing mutations through
the BE or the CREs were not significantly repressed by AR,
demonstrating the importance of these sites in AR-mediated repression.
It is important to note that the activity of each promoter mutant was
typically more than 150-fold greater than a promoterless control (19).
Thus, loss of repression is not the result of promoter constructs being
compromised to such an extent that no further reduction in promoter
activity is possible, but rather a result of the specific mutations in
the BE and CREs.
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BE and the tandem CREs must
be present. Recently, we reported that a number of transcription
factors in the cAMP response element binding protein/activating
transcription factor (ATF) family, including cAMP response element
binding protein, cAMP response element modulator protein, ATF1, ATF2,
and Jun, bind the CREs in the human -subunit promoter (20).
Additional studies showed that a natural CRE variant having a single
point mutation in the core palindrome (TGACGTCA to
TGATGCTA) is active in gonadotropes but binds only Jun and
ATF2. Interestingly, in the presence of AR, a promoter containing the
variant CRE(-1500 TGAT) is repressed to the same extent as a promoter
containing the palindromic CRE (-1500 WT). This demonstrates that Jun
and ATF2 are included in the subset of transcription factors required
for promoter repression by AR (Fig. 4).
Since the variant CRE is present in all species other than primates,
the data suggest that AR-mediated repression of the -subunit is not
limited to primates.
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-subunit gene, we addressed whether specific
domains of AR are required for repression. Most structure-function
studies of AR have focused on determining the regions of the receptor
required for stimulation of transcription. Thus, by identifying the
regions of the receptor required for repression, we not only learn
about the mechanism of -subunit gene regulation but also about the
functional determinants required for the suppressive effects of AR.
To establish receptor requirements for repression, a variety of mutant
ARs were cotransfected with the wild type -1500-bp luciferase reporter
construct. ARs having deletions that span the amino-terminal domain
(14–150, 142–337, 338–499, 500–558) retained their
ability to repress -subunit promoter activity (Fig. 5A). Thus, repression does not require
regions within the amino terminus of AR. In contrast, deletion of the
DBD (538–614) or the LBD (660–919) eliminated AR-dependent
repression, indicating that these two domains are critical. The
requirement for the DBD was further substantiated using a point mutant
that has a cysteine-to-alanine mutation within the first zinc finger
(C576A). This mutation, which disrupts DNA-binding activity, eliminated
repression by the receptor. A fourth mutation, which deletes the
nuclear localization signal (615–633), also prevents promoter
repression. Since this mutant is poorly translocated into the nucleus,
it is unclear whether this region is directly involved in repression
(21). Together, these studies identify two distinct domains of AR that
are required for suppression of the -subunit promoter; namely, the
DBD and the LBD.
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142–337, Fig. 5B). An intact DBD is also essential.
Minor roles in activation by a second region within the amino terminus
[amino acids (aa) 338–499] and the LBD are suggested by the less
than optimal activation response when these regions are deleted.
Importantly, Western blot analysis confirmed that each of these mutant
receptors are expressed in transfected T3 cells (Fig. 5C). These
findings are consistent with previously reported studies on activation
of transcription by AR (21, 22).
To further validate the involvement of the DBD and LBD in repression of
- subunit promoter activity, we cotransfected the wild type
-1500-bp reporter construct with two additional mutants, one
containing only the DBD (aa 507–660) and the other the DBD plus the
LBD (aa 507–919). Both constructs were fully capable of promoter
repression (Fig. 6A). In contrast, they
were incapable of stimulating mouse mammary tumor virus (MMTV) promoter
activity (Fig. 6B). On the basis of these data, it is tempting to
conclude that the DBD alone contains the necessary information required
for suppression of -subunit promoter activity. It is important to
recognize, however, that this is only true when the amino-terminal
domain of AR is absent, as a construct missing only the LBD fails to
repress (660–919; Fig. 5B). Thus, in the context of the entire
receptor, both the DBD and LBD are required for suppression of
transcription.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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-subunit promoter from other promoters negatively regulated by
AR, suggesting that transcriptional repression by AR can occur through
multiple mechanisms that depend on promoter context. As far as we know,
this is the first example of steroid receptor-dependent negative
regulation being mediated by a paired combination of regulatory
elements that bind other specific transcription factors.
Multiple examples exist in the literature whereby nuclear receptors
repress promoter activity by interfering with other transcription
factors. In most cases, members of the Fos/Jun/ATF family, the Oct
family, and NF-
B appear to be targets for transcriptional
interference (32, 33). With the glucocorticoid receptor (GR), in
vitro data suggest that repression is the result of direct
interaction between components of the AP-1 complex, Fos and Jun, and GR
(32, 34, 35). However, this mechanism has not been confirmed in
vivo.
Even though the -subunit promoter contains a high-affinity binding
site for AR (9), our present study clearly establishes that this site
does not mediate the negative transcriptional effect of androgens.
Instead, two other regulatory elements (BE and the tandem CREs)
appear to be the targets for androgen-dependent negative regulation of
the -subunit promoter. The involvement of the CREs in AR repression
suggests that AR may directly interact with members binding this
element. Repression of the variant CRE, which binds only Jun and ATF2,
further implicates these proteins in interactions with AR. Such a
mechanism is supported by earlier finding of Kallio et al.,
who showed that AR inhibited c-Jun binding to an AP-1 site in vector
DNA sequences (31). This information, together with the data on
interactions between GR and c-jun, implicates
c-jun as a common target for members of the steroid receptor
family.
Although interaction between AR and c-jun may be important
for the CRE involvement associated with repression of the -subunit
promoter, it clearly cannot fully explain the mechanism, since an
additional element (BE) is also required for AR-dependent
suppression. The mutation that established the involvement of BE in
AR repression spans from -319 to -291 of the -subunit promoter.
This region was previously shown to contain two response elements
important for promoter activity, BE1 and BE2 (19). Analysis of
smaller mutations within each of these elements revealed that full
response to AR requires that both elements be present (data not shown).
Furthermore, earlier studies on the -subunit promoter in
gonadotropes revealed that complex interactions occur between proteins
binding the BE and CREs. This suggested that a shared coactivator
may be involved in transducing the transcriptional signal from the
proteins that bind BE and the CREs (19, 20). Such a mechanism may
help explain the requirement for two response elements in androgen
repression by invoking this intermediate or coactivator as a target for
AR.
Several recent reports indicate that the LBDs of multiple nuclear
receptors interact with the CREB-binding protein, CBP, a coactivator
required for activation of both CREB and AP-1 (36, 37, 38). This suggested
that repression of AP-1 activity by steroid receptors results from a
competition for limiting amounts of CBP. In this regard, participation
of the CREs in transcriptional repression of the -subunit gene also
implicates CBP, or other coactivator that interacts with proteins
binding the BE and CREs, as a possible target for the observed
promoter effects.
The co-requirement for BE in AR-dependent suppression of -subunit
promoter activity is of interest in light of an even more recent report
indicating that AR negatively regulates matrix metalloproteinase-I
expression not through AP-1 but through a family of Ets-related
transcription factors that are also required for positive regulation
(29). This study revealed a direct protein-protein interaction between
an Ets protein and AR. Interestingly, within BE there is an Ets
protein-binding site. Despite our earlier findings that the Ets site is
not required for basal promoter activity (19), it remains possible that
interactions with an Ets protein at this site may be a prerequisite for
promoter repression. Thus, the need for two distinct elements may be
explained through a mechanism in which AR is coupled to the promoter
via the Ets protein and brought into proximity of the CRE and thereby
facilitates its interference of the transcription factors bound to that
element.
Another important feature of our study is the demonstration that
repression of the -subunit promoter requires two distinct domains of
AR: the DBD and the LBD. Although both domains are required in the
context of the full-length receptor, the DBD alone can function as an
efficient repressor when isolated from both the amino-terminal domain
and the LBD. This suggests that, in the presence of ligand, the LBD may
prevent the amino-terminal half of the receptor from masking the
suppressive activity of AR that resides within the DBD. The requirement
for ligand in AR-dependent repression of the -subunit promoter was
previously established (9). Two other reports have identified regions
of AR required for repression and differ from our study in that
repression domains within the amino terminus of AR were identified (29, 31). In one study, the amino terminus (aa 38 and 296), the LBD, and the
DBD (point mutation C562G) were all implicated as important for
transcriptional repression by AR (31). A more recent report concluded
that repression required multiple redundant domains in the amino
terminus (29). One such domain, encompassing aa 510–536, was deemed
sufficient for repression. All of our constructs with repressive
activity contained this domain or other potential redundant sequences.
Our experiments, therefore, did not directly test whether a redundant
amino-terminal domain of AR is required for suppression of - subunit
promoter activity.
Although both activation and repression require an AR with an intact
DBD and LBD, there are some important distinctions in the use of these
domains. In activation, the DBD functions to bind the receptor to a
response element, differing from its function in -subunit repression
where direct binding to a promoter-regulatory element is not required.
The LBD also plays a role in both activation and repression. In our
studies, removal of the LBD eliminates repression by the receptor. In
contrast, with activation, the receptor is still capable of
constitutive activity but to a lesser extent than the wild type.
Importantly, there is a discrete domain within the amino-terminal
region of AR that is required for activation that does not participate
in repression, further underscoring that there are domain-specific
differences in the stimulatory and repressive properties of AR. Our
goal now is to further elucidate the roles of the DBD and LBD in
repression of the -subunit gene.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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DNA
All plasmid DNAs were prepared from overnight bacterial cultures
using Qiagen DNA plasmid columns according to the supplier’s protocol
(Qiagen, Chatsworth, CA). Oligonucleotides were purchased from Midland
Scientific (Midland, Texas).
Purified AR and Antibody
Bacterially expressed and purified rat AR DBD (aa residues
460–704, rAR-DBD) was prepared as previously described (39). The
antibody (AR52) used in the electrophoretic mobility shift assays is
directed against an epitope (aa residues 527–541) that maps to exon B
of the rat AR (41).
Clones
Generation of the human -subunit promoter constructs was
described previously (19, 20). Clones containing mutations in the PGBE,
BE, GSE, URE, CRE, and ARE were described previously as µ7, µ8,
µ11, µ13, µ14, and µ15, respectively (19). The -1500 TGAT
promoter construct is described elsewhere (20). Wild type human AR
expression vector consists of the full-length AR cDNA fused to the CMV
promoter (39). All AR mutants and GH are expressed from the CMV
promoter. CMV-GH (43), AR mutants 507–660, 507–919, 1–660, (22), hAR
142–337 (44), 338–499 (45) and hAR(C576A), 14–150,
615–633, 538–614 (21) are described. 500–558 was
constructed similarly to those described elsewhere (22). MMTV-Luc was
generated by isolating a 2710 NheI/BamHI fragment
containing the luciferase gene and SV40 sequences from pGL2-Basic
(Promega, Madison, WI) and subcloning them into the
NheI/BamHI sites downstream of the MMTV long
terminal repeat in pMAMneo (CLONTECH, Palo Alto, CA). This resulted in
the removal of a 3566-bp fragment from the pMAMneo vector containing
the Neor cassette and most of the SV40 sequences.
Cell Culture and Transfections
T3 cells were grown in DMEM supplemented with 5% FBS, 5%
horse serum, penicillin, and streptomycin (GIBCO, Grand Island, NY)
(46). Transfection and enzyme assays were performed as described
previously (19). Briefly, each luciferase construct (1.25 µg) was
cotransfected with 60 ng of either CMV-GH or pCMVhAR expression vectors
and 0.42 µg RSV-ß-galactosidase using 5 µl lipofectamine. The
lipofectamine/DNA solution was replaced with complete medium containing
100 nM DHT after 12–16 h. Cells were harvested 48 h
later using 150 µl of lysis buffer (Promega). Luciferase activity was
quantified by luminescence using 10–20 µl lysate and 100 µl
luciferase assay reagent (Promega). ß-Galactosidase activity was
quantified also by luminescence using the Galacto-light assay system
(Tropix, Bedford, MA). For each sample, the
luciferase/ß-galactosidase activity of each construct was normalized
to the luciferase/ß-galactosidase activity of the wild type promoter
in the presence of CMV-GH. The values were then averaged over a minimum
of three independent experiments.
Electrophoretic Mobility Shift Analysis and Supershift
Analysis
Preparation of nuclear extracts (47) and electrophoretic
mobility shift analysis were done as previously described (9, 19).
Briefly, rAR-DBD (100 ng) was preincubated at 4 C for 15 min in binding
buffer (12.5 mM HEPES, pH 7.9, 25 mM KCl, 10
mM MgCl2, 10% glycerol, 0.5% Triton X-100,
0.5 mM dithiothreitol) with 1 µg of
poly(deoxyinosinic-deoxycytidylic)acid and 200 ng each of
Escherichia coli DNA and salmon sperm DNA. Approximately 10
fmol of probe were added to the reaction, and binding was allowed to
proceed for 10 min at 4 C. Subsequently, 1 µg of anti-AR DBD
antibody, AR-52, was added to the appropriate binding reactions, and
incubations were continued for an additional 20 min at room
temperature. An oligonucleotide containing the sequence for the
-subunit promoter ARE (5'-GTCATGGTAATTACACCAAGRACCCTTCAA-3') was
added to indicated reactions at a concentration 200x that of added
probe. Competitor was added to the reaction before the addition of
probe. After an additional incubation for 20 min at 4 C, samples were
subjected to electrophoresis in 4% polyacrylamide gels (0.5x
Tris-borate-EDTA) at 4 C for 4–5 h. Gels were dried and visualized by
autoradiography.
Western Blot Analysis
Expression plasmids (15 µg) were transfected into T3 cells
seeded onto 100-mm plates at a density of 1.5 x 106
cells per plate as described above. After 48 h, cells were
harvested by washing two times in PBS, adding 1 ml of TEN buffer (40
mM Tris, 7.5, 1 mM EDTA, 150 mM
NaCl) and incubating at room temperature for 5 min. Cells were removed
from the plates, pelleted, and resuspended in 150 µl 0.25
M Tris-HCl (7.8). Cells were lysed by a series of three
freeze-thaw cycles, the debris was removed by centrifugation, and the
supernatant was assayed for protein. Lysate (40 µg) was resolved on
an SDS-PAGE gel using a 4% stacking gel and a 10% resolving gel as
described elsewhere (19). Proteins were then transferred to a
nitrocellulose membrane (Schleicher & Schuell, Keene, NH) and rinsed in
a solution of PBS-Tween (0.1% Tween 20 in PBS). The membrane was
blocked using blotto (0.1% Tween, 5% Carnation nonfat dry milk,
0.02% sodium azide in PBS) at room temperature for 8 h and then
incubated with the AR antibody AR52 at a dilution of 1:2000 in blotto
overnight at room temperature. The membrane was rinsed two times for 15
min each at room temperature in PBS-Tween and then incubated with the
secondary antibody (anti-rabbit horseradish peroxidase 1:7500, Santa
Cruz Biotechnology, Santa Cruz, CA) for 2 h at room temperature in
blotto. Membranes were washed in PBS-Tween twice for 5 min, once for 25
min, and twice for 10 min followed by one quick rinse in PBS alone.
Proteins were visualized by chemiluminescence using the enhanced
chemiluminescence Western blotting detection reagents by Amersham
(Arlington Heights, IL).
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FOOTNOTES |
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This work was supported by NIH Grants DK-28559 and HD-34032 (to J.H.N.) and DK-08975–02 (to L.L.H.).
Received for publication May 7, 1997. Accepted for publication June 18, 1997.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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J. M. Grad, L. S. Lyons, D. M. Robins, and K. L. Burnstein The Androgen Receptor (AR) Amino-Terminus Imposes Androgen-Specific Regulation of AR Gene Expression via an Exonic Enhancer Endocrinology, March 1, 2001; 142(3): 1107 - 1116. [Abstract] [Full Text] [PDF]
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J. J. Brosens, N. Hayashi, and J. O. White Progesterone Receptor Regulates Decidual Prolactin Expression in Differentiating Human Endometrial Stromal Cells Endocrinology, October 1, 1999; 140(10): 4809 - 4820. [Abstract] [Full Text]
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R. A. Abbud, R. K. Ameduri, J. S. Rao, T. M. Nett, and J. H. Nilson Chronic Hypersecretion of Luteinizing Hormone in Transgenic Mice Selectively Alters Responsiveness of the {alpha}-Subunit Gene to Gonadotropin-Releasing Hormone and Estrogens Mol. Endocrinol., September 1, 1999; 13(9): 1449 - 1459. [Abstract] [Full Text]
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S. Kawakami and S. J. Winters Regulation of Lutenizing Hormone Secretion and Subunit Messenger Ribonucleic Acid Expression by Gonadal Steroids in Perifused Pituitary Cells from Male Monkeys and Rats Endocrinology, August 1, 1999; 140(8): 3587 - 3593. [Abstract] [Full Text]
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P. Aarnisalo, H. Santti, H. Poukka, J. J. Palvimo, and O. A. Jänne Transcription Activating and Repressing Functions of the Androgen Receptor Are Differentially Influenced by Mutations in the Deoxyribonucleic Acid-Binding Domain Endocrinology, July 1, 1999; 140(7): 3097 - 3105. [Abstract] [Full Text]
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J. L. Turgeon and D. W. Waring Androgen Modulation of Luteinizing Hormone Secretion by Female Rat Gonadotropes Endocrinology, April 1, 1999; 140(4): 1767 - 1774. [Abstract] [Full Text]
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P.-Z. Tang, C. H. Tsai-Morris, and M. L. Dufau Regulation of 3{beta}-Hydroxysteroid Dehydrogenase in Gonadotropin-Induced Steroidogenic Desensitization of Leydig Cells Endocrinology, November 1, 1998; 139(11): 4496 - 4505. [Abstract] [Full Text] [PDF]
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J. Lindzey, W. C. Wetsel, J. F. Couse, T. Stoker, R. Cooper, and K. S. Korach Effects of Castration and Chronic Steroid Treatments on Hypothalamic Gonadotropin-Releasing Hormone Content and Pituitary Gonadotropins in Male Wild-Type and Estrogen Receptor-{alpha} Knockout Mice Endocrinology, October 1, 1998; 139(10): 4092 - 4101. [Abstract] [Full Text] [PDF]
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 C. S. Song, M. H. Jung, S. C. Kim, T. Hassan, A. K. Roy, and B. Chatterjee Tissue-specific and Androgen-repressible Regulation of the Rat Dehydroepiandrosterone Sulfotransferase Gene Promoter J. Biol. Chem., August 21, 1998; 273(34): 21856 - 21866. [Abstract] [Full Text] [PDF]
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 P. Aarnisalo, J. J. Palvimo, and O. A. Janne CREB-binding protein in androgen receptor-mediated signaling PNAS, March 3, 1998; 95(5): 2122 - 2127. [Abstract] [Full Text] [PDF]
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