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Signaling in Anterior Pituitary Cells1
Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037
Address all correspondence and requests for reprints to: Louise M. Bilezikjian, Ph.D., Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037. E-mail: bilezikjian{at}salk.edu
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Abstract |
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(TGF) are crucial
autocrine, paracrine, and endocrine modulators of anterior pituitary
function. Activins regulate most pituitary cells and lactotropes are
targets of TGF. Smad2 and Smad3 are two cellular mediators of
activin/TGF signaling, whereas Smad7 is as an inducible, negative
modulator of the pathway. This study was undertaken to evaluate Smad7
regulation in the pituitary. Activin A rapidly and transiently
increased Smad7 messenger RNA (mRNA) levels of rat anterior pituitary
(RAP), clonal gonadotrope (
T3–1 and LT2), and corticotrope
(AtT20) cells with an EC50 of 0.1–0.2 nM. In
RAP cells, activin A or TGF1 had equivalent effects that were
additive. Follistatin, known to bind and inactivate activins, prevented
Smad7 induction by activin. Inhibin A partially antagonized activin A,
perhaps reflecting gonadotrope-selective actions. This antagonism
was also evident with T3–1 and LT2 gonadotropes. Forskolin had
no measurable effect in RAP cells, but increased Smad7 mRNA levels in
T3–1 cells and decreased them in LT2 cells. Transient
transfection of Smad7 along with 3TPLux, an activin/TGF-responsive
reporter, blocked activin-mediated promoter activation in T3–1 and
AtT20 cells. In T3–1 cells, which express endogenous follistatin
mRNA, a follistatin-luciferase reporter, rFS(rin3)-Luc, was
transcriptionally activated by activin A, or when cotransfected with a
constitutively active ActRIB [Alk4(T>D)], Smad2, or Smad3. Smad7
blocked rFS(rin3)-Luc activation by activin A or Alk4(T>D). Together,
these results point to a role of Smad7 in modulating activin/TGF
signaling in the pituitary. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(TGF) family of growth and
differentiation factors have been recently recognized as a class of
important modulators of anterior pituitary function and organogenesis
(1, 2, 3, 4, 5, 6, 7, 8). Activins are homo/heterodimers of inhibin/activin
A- and B-subunits
(5). They were initially characterized as gonadal feedback
regulators of FSH secretion, but now are known to be as widely
distributed as other TGF family members and to regulate a broad
spectrum of biological functions (1, 5, 9, 10). The
actions of activins, in turn, are modulated by two known functional
endogenous antagonists, inhibins and follistatins (1, 2, 3, 5, 6, 11, 12). Inhibins are generated by the heterodimerization of
either of the two inhibin/activin -subunits with the structurally
related inhibin/activin . Their biological actions seem to require
specific inhibin-binding sites (13, 14), and two such
candidate molecules were recently characterized. One of these is the
previously identified type III TGF receptor, betaglycan, recently
shown to bind inhibin A with high affinity and confer inhibin
responsiveness to cells (15). Another membrane
glycoprotein, p120, was purified from bovine pituitary membranes and
was shown to be expressed by inhibin-responsive tissues
(16). In contrast to inhibins, whose actions are limited
to cells that express cell surface inhibin-binding components,
follistatins are structurally unrelated activin-binding glycoproteins
that biologically inactivate the activins (2, 3, 6, 12).
Activins regulate the function of multiple pituitary cell types,
including gonadotropes, somatotropes, and corticotropes
(17, 18, 19, 20, 21, 22). By contrast, lactotropes may be targets of both
activins and TGF (21, 23, 24, 25), whereas the effects of
inhibins are gonadotrope specific (5, 13, 14). Activins
(26, 27, 28), follistatins (29, 30, 31), TGF1
(25), and, possibly, inhibins (6) are
secretory products of pituitary cells, where they exert cell-specific
autocrine/paracrine effects (28, 31).
The interaction of two types of receptors with cytoplasmic
serine/threonine-specific protein kinase domains is required for the
transduction of signals generated by the TGF family of growth
factors (9, 32, 33). Activin effects are mediated by one
of two known type II receptors (ActRII and ActRIIB) and one type I
receptor (ActRIB or Alk-4) (34, 35, 36, 37), whereas TRII and
TRI (Alk-5) mediate TGF effects (9, 32, 33). The
signaling cascade is initiated upon binding of the ligand to a type II
receptor followed by recruitment and trans-phosphorylation
of type I by type II receptors (9, 32, 33). Type I
receptors, in turn, transiently bind and phosphorylate a class of
downstream signaling substrates known as pathway-specific Smads,
which then associate with another Smad, Smad4/DPC4, a signaling
molecule that seems to be shared by the TGF family of ligands
(9, 38, 39, 40). The activated heteromeric Smad complexes
translocate into the nucleus, where they interact with cognate DNA
sequences to regulate the expression of target genes (9, 38, 39, 40). This process is itself modulated by the association of
a subclass of inhibitory Smad proteins, Smad6 and Smad7, with type I
receptors to block the phosphorylation-dependent activation of
pathway-specific Smads (41, 42, 43, 44). Although activins and
TGF produce a distinct set of cellular responses via their
corresponding cell surface receptors, the two ligands appear to share
the signal transduction function of the two pathway-restricted Smad
proteins, Smad2 and Smad3 (45, 46, 47, 48). Similarly, the
inhibitory Smad7 functions as a downstream modulator of the actions of
both activins and TGF (41, 42, 43, 44), whereas Smad6 may be
more important for the modulation of bone morphogenetic protein
(BMP) signaling (49). The activation of
pathway-restricted Smads involves the phosphorylation of an SSXS motif
in the C-terminal domain to remove an inhibitory action of the N-domain
and allow them to form oligomeric complexes (9, 38, 39, 40).
By contrast, negative feedback modulation of signaling by inhibitory
Smads seems to require their rapid and inducible expression. The
messenger RNA (mRNA) for Smad7 is rapidly induced in response to
activin or TGF by a transcriptional mechanism (50, 51),
and overexpression of the proteins can block ligand-induced cellular
responses (41, 42, 44, 49, 52). It is well established
that activins and TGF regulate many aspects of anterior pituitary
function, but a role for Smad7 in this tissue has not been previously
demonstrated. The present study was undertaken to evaluate the
participation of Smad7 as a modulator of pituitary activin and TGF
actions. The results show that both ligands rapidly induce Smad7 mRNA
levels of rat anterior pituitary cultures and cell lines derived from
the anterior pituitary and that Smad7 protein can modulate
ligand-dependent transcriptional responses of these cells. These
results are consistent with an important function of Smad7 in the
pituitary.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PJ) supplemented with 2% FBS
and appropriate growth factors (53). Cells were maintained
at 37 C in 7.5% CO2 and 92.5% air. Before
initiating the experiments, the cells were washed three times with
PJ medium supplemented with only 0.2% FBS and growth factors, then
allowed to equilibrate for 24 h. After two more washes and an
equilibration period of 2–3 h, test substances were added at the
indicated concentrations and incubation times. Mouse corticotropic
AtT20 (18) and gonadotropic T3–1 (54) or
LT2 (55, 56) cell lines were grown in complete medium
(DMEM supplemented with 10% FBS and 2 mM glutamine). For
the evaluation of Smad7 mRNA, the cells were cultured in 6-cm dishes
and allowed to grow to confluence. At this time, they were washed in
medium containing 2% FBS. After 24 h of equilibration, the cells
were given fresh medium and treated after another equilibration period
of 3–4 h. For transcriptional studies, AtT20 and T3–1 cells were
plated in 12-well tissue culture plates and processed as described
below. For FSH secretion studies, LT2 cells were cultured in 12-well
tissue cultures plates until they were 70–80% confluent. The cells
were equilibrated in medium with 2% FBS for 24 h before
introducing activin A, with or without inhibin A. The amount of FSH was
quantified by RIA with reagents provided by Dr. Parlow through the
National Pituitary and Hormone Distribution Program at NIDDK. All
treatments were performed in triplicate and repeated at least three
times.
Ribonuclease protection
The rat Smad7 complementary DNA (cDNA) template used to
synthesize an antisense riboprobe was constructed by subcloning a
ClaI/XhoI fragment, encoding amino acids
197–271, into pBluescript KS (Stratagene, La Jolla, CA).
The plasmid was linearized with SalI and an antisense
riboprobe was synthesized using T3 RNA polymerase to yield a protected
fragment of 217 nucleotides. The mouse Smad7 cDNA (41) was
linearized with EcoRV, and an antisense riboprobe that would
protect approximately 500 nt was synthesized using SP6 RNA polymerase.
Rat and mouse glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
antisense riboprobes were synthesized using T3 RNA polymerase to yield
a protected fragment of 134 nucleotides and used as internal controls.
All probes were synthesized in the presence of
[-32P]UTP (3000 Ci/mmol) and 20
µM UTP, with the exception of GAPDH, which was
labeled to a lower specific activity by the inclusion of 200
µM UTP. Total RNA was extracted with the RNeasy
kit (QIAGEN, Hilden, Germany), and 30–50 µg were used
to evaluate Smad7 mRNA levels, essentially as previously described
(57). The samples were resolved on 5% polyacrylamide/8
M urea gels. Quantitative analysis was performed
using the PhosphorImager system (Molecular Dynamics, Inc.,
Sunnyvale, CA) and the ImageQuant 4.0 software package. The reported
data reflect Smad7 levels normalized to the internal GAPDH control. An
image of a typical gel is shown in Fig. 1
. Each treatment was performed in
triplicate wells or dishes, and experiments were replicated at least
three times. Results are reported as means of normalized data from
multiple independent determinations, analyzed using ANOVA and
Student’s t test for individual comparisons.
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-responsive 3TPLux luciferase reporter has
been previously described (58) (provided by Dr. Joan
Massagué). The rat follistatin luciferase reporter plasmid,
rFS(rin3)-Luc, retaining most of the first three introns, all of exons
2 and 3, but excluding the first exon, was constructed as follows. A
genomic KpnI/EcoI fragment of 2.87-kb upstream
and 136-bp downstream sequence relative to the major transcriptional
initiation site (59) was subcloned into the
KpnI/SmaI site of the pGL2 basic luciferase
reporter vector (Promega Corp., Madison, WI) by blunting
the EcoI restriction end. Another approximately 2.6-kb
SalI/BglII genomic fragment spanning most of the
first intron to the middle of intron 3 was placed immediately
downstream of the -2.87/+136 fragment by insertion into a
XhoI/BglII site. Mouse AtT20 and T3–1 cells
were trypsinized and plated at a density of 2.5 x
105 cells/well in 2 ml complete medium 24 h
before transfection. The cells were transfected in complete medium with
0.7 µg luciferase reporter plasmid, 0.1 µg
cytomegalovirus--galactosidase (-GAL) and 0.7 µg of either
vector only or the appropriate Smad plasmids. Transfections were
performed under optimized conditions using the Superfect Transfection
Reagent (QIAGEN). After 2.5 h of incubation with
various plasmid DNAs, the cells were washed and allowed to recover for
3–4 h in DMEM containing 2% FBS and 2 mM
glutamine. The cells were treated or untreated with activin A for
16–18 h and harvested in lysis buffer [1% Triton X-100, 25
mM glycylglycine (pH 7.8), 15
mM MgSO4, 4
mM EGTA, and 1 mM
dithiothreitol]. Luciferase reporter activity was evaluated by
normalizing to relative -GAL activities.
Reagents
Recombinant human activin A and inhibin A were provided by
Genentech, Inc. (San Francisco, CA), and rhFS288 was
obtained through the National Hormone and Pituitary Program of NIDDK.
Recombinant human TGF1 was purchased from Calbiochem
(San Diego, CA). GnRH was synthesized and provided by Dr. Jean Rivier
(The Salk Institute, La Jolla, CA). The expression vector for
Xenopus Smad2 (60) was provided by Dr. Douglas
Melton (Harvard University, Cambridge, MA), and the mouse Smad7 cDNA
(41) was obtained from Dr. Peter ten Dijke (Ludwig
Institute for Cancer Research, Uppsala, Sweden). The cDNA expression
plasmids for rSmad3 (46) and Alk4(T>D) (61, 62) have been previously described. The rat Smad7 homologue was
obtained by screening a rat brain cDNA library using mouse Smad7 cDNA
as a probe.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). This effect of activin A was
concentration dependent, as measured at the 1 h point (Fig. 2B).
To assess the effect of activin A on Smad7 mRNA levels in distinct
pituitary cell populations, experiments were performed with
activin-responsive clonal pituitary cell lines, T3–1 and LT2
gonadotropes, and AtT20 corticotropes. The time-course and the
concentration dependence for activin A to induce Smad7 mRNA in the cell
lines were similar to those seen with primary cultures of rat anterior
pituitary cells (Fig. 2, C–H).
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). Inhibin A
(3.5 nM) attenuated the effect of all concentrations of
activin A on Smad7 mRNA accumulation when it was added to cultured rat
anterior pituitary cells 3–4 h before treatment with activin A (Fig. 4A). The same concentration of inhibin A
had a negligible effect when it was introduced to cells simultaneously
with activin A (data not shown). As the antagonistic effect of inhibin
A on pituitary cells most likely reflects actions on gonadotropes, two
gonadotrope cell lines were evaluated for their ability to respond to
inhibin A. As in cultured rat anterior pituitary cells, pretreatment of
T3–1 and LT2 mouse gonadotrope cell lines with inhibin A for
3–4 h partially antagonized the action of activin A on Smad7 mRNA
induction (Fig. 4, B and C). However, in contrast to primary rat
anterior pituitary cells, where the effect of inhibin A was primarily
to blunt the magnitude of the response to activin A, inhibin A appeared
to diminish the sensitivity of T3–1 and LT2 cells to activin A.
These effects of inhibin A on activin-induced Smad7 mRNA accumulation
closely mirrored its effects on FSH secretion from RAP cells, as
previously reported (5), and from LT2 cells (Fig. 5). Inhibin effects were not evaluated in
AtT20 cells because they are unresponsive to its actions (15, 18).
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and other signal
transduction pathways on Smad7 mRNA expression were evaluated in
cultured rat anterior pituitary cells. A maximal concentration of
TGF1 (0.1 nM) increased Smad7 mRNA levels to the same
extent as a maximal concentration of activin A (0.7 nM;
Fig. 6). The effects of the two agents
were additive when added simultaneously to cells, suggesting that they
activate distinct ligand-dependent pathways, possibly in different cell
populations of the pituitary. Forskolin, which activates cAMP-dependent
pathways, had no effect on Smad7 mRNA levels of primary cultures of rat
anterior pituitary cells. However, in contrast to primary cells,
forskolin increased Smad7 mRNA levels of T3–1 cells 3-fold and
decreased those of LT2 cells 30% (Fig. 7). Agents such as GnRH or
12-O-tetraphorbol 12-myristate 13-acetate (TPA),
which activate phosphatidyl inositol turnover and protein kinase C, had
no statistically significant effect on Smad7 mRNA levels in any of the
cell types evaluated (Fig. 7).
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-responsive luciferase reporter, 3TPLux, in
both AtT20 and T3–1 cells (Fig. 8).
Cotransfection of a Smad7 expression plasmid along with 3TPLux had no
statistically significant effect on basal transcription, but
substantially reduced the ability of activin A to stimulate the 3TPLux
promoter (Fig. 8). Parallel Western blot analyses confirmed that Smad7
protein was expressed in these transient transfection experiments (data
not shown). The mediation of activin signaling by Smad2 or Smad3 and
its modulation by Smad7 were further evaluated by assessing their role
in the regulation of follistatin expression in T3–1 cells. In this
gonadotrope cell line, as in primary rat anterior pituitary cell
cultures, endogenous follistatin expression is transcriptionally
regulated by activin A (57, 63). Activin A (1
nM) transcriptionally stimulated the promoter of a
follistatin-luciferase reporter plasmid harboring activin-responsive
elements, rFS(rin3)-Luc, when transiently transfected into T3–1
cells (Fig. 9). Coexpression of Smad7
almost completely blocked this action of activin A, indicating a role
for Smad7 in the modulation of follistatin gene transcription in
T3–1 cells (Fig. 9). To confirm that signal transduction by type IB
(Alk-4) activin receptor is sufficient for the transcriptional
activation of the follistatin gene and that these effects are mediated
by Smad2 or Smad3, the effects of these components of the activin
signaling cascade on rFS(rin3)-Luc activity were evaluated.
Cotransfecting Smad2 or Smad3 with rFS(rin3)-Luc increased baseline
luciferase activity 4- or 5-fold, respectively, and this was further
enhanced by treatment with 1 nM activin A (Fig. 9).
Similarly, rFS(rin3)-Luc transcription was stimulated by a
constitutively active type IB activin receptor, Alk4(T>D)
(61). The latter was also blocked by Smad7, confirming
mediation by Smad proteins (Fig. 9).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. The data suggest that in addition to its ability to directly
inhibit activins/TGF signal transduction, Smad7 can modify activin
tone indirectly by regulating the expression of the activin-binding
protein, follistatin. Activin A or TGF1 rapidly stimulated Smad7
mRNA accumulation in primary cultures of rat anterior pituitary cells,
indicating that it is a downstream target of pituitary receptors for
both ligands. The two ligands produced an additive effect when added
together, consistent with the current model that Smad7 is shared as a
negative modulator of both activin and TGF signaling pathways
(41, 42, 43, 44). This additivity most likely reflects the
induction of Smad7 mRNA in distinct cell populations that are targets
of each ligand. Activin probably affects Smad7 mRNA levels in multiple
cell types known to respond to this ligand (17, 18, 19, 20, 21, 22). By
contrast, the effects of TGF may be specific to lactotropes
(21, 23, 24, 25). Nonetheless, the possibility that activin
and TGF1 modulate Smad7 mRNA levels in overlapping cell populations
by activating their respective ligand-specific pathways via specific
type I and type II receptors cannot be excluded at this time
(9).
The transcriptional studies reported in this study provide further
confirmation of a functional role for Smad7 in the modulation of
activin responses at least in two cell types, gonadotropes and
corticotropes. The fact that Smad7 suppressed transcriptional
activation of both 3TPLux and rFS(rin3)-Luc constructs in response
to either activin A or by the expression of a constitutively active
type IB/Alk-4 activin receptor, Alk4(T>D) (61) suggests
that it functions downstream of type I receptors that mediate activin
effects. This is further supported by the ability of two
pathway-restricted mediators of activin or TGF effects, Smad2 and
Smad3, to stimulate transcription of the follistatin gene to the same
extent as activin A.
Activin A increased Smad7 mRNA levels of primary rat anterior pituitary
cells and cell lines derived from gonadotropes (T3–1 and LT2)
and corticotropes (AtT20) over the same concentration range. This is in
agreement with concentrations of activin A required for the regulation
of hormone secretion from various cell types of the anterior pituitary
(5). The main difference among the cells was the magnitude
of their response to activin A, with the largest response seen in AtT20
cells. Whether this reflects cell-specific differences in
mRNA-stabilizing mechanisms that are exhibited by the normal pituitary
counterparts is not currently known. Elucidation of the exact
biological significance of these observations will have to await the
availability of sensitive and specific reagents that permit correlative
studies of Smad7 mRNA and protein levels. Interestingly, as opposed to
gonadotropes represented by T3–1 and LT2 cells, AtT20
corticotropic cells represent one of two populations of pituitary cells
(corticotropes and somatotropes) in which activin exerts inhibitory
effects on hormone production. Yet, activin induced Smad7 in both cell
types, regardless of whether it inhibits or stimulates hormone
production. This suggests that activin suppresses ACTH and GH
production by Smad-dependent activation of inhibitory target genes, by
altering the expression of cell-specific factors required for hormone
production, or by mechanisms that are not dependent on signal
transduction via Smads.
The induction of Smad7 mRNA in response to activin A was rapid and
transient, as reported for activin A and TGF in several other cell
lines (41, 42, 44). The mechanism underlying the transient
nature of the response is unknown, but could reflect mRNA
destabilization, the disruption of transcriptional activation of the
Smad7 gene, or the inactivation of signal transduction. Experiments
with protein synthesis inhibitors seem to favor the former two
possibilities (41).
Gonadotropes of the anterior pituitary are the only cell type of this
tissue known to respond to inhibins (5). In agreement,
inhibin A functionally antagonized the effect of activin A on T3–1
and LT2 Smad7 mRNA levels in a competitive manner, similar to its
suppressive action on activin-stimulated FSH production from primary
gonadotropes (5) and LT2 cells. Given that gonadotropes
comprise only 5–10% of the total cell population, the ability of
inhibin A to attenuate as much as 30% of the activin A effect was
surprising. Perhaps this can be explained by the possibility that
gonadotropes contribute to a significant portion of the Smad7 mRNA
signal in primary cultures of rat anterior pituitary cells or that the
pituitary contains other inhibin-responsive cells.
The effect of activin A was prevented when it was preincubated with the truncated splice variant of follistatin, recombinant human (rh) FS288 (64), at a molar ratio of at least 2:1 of rhFS288/activin A. Interestingly, rhFS288 was effective in blocking the action of activin A on Smad7 mRNA only if the two factors were preincubated, presumably to allow sufficient time for the formation of stable rhFS288:activin A complexes. When the same molar ratio of rhFS288 and activin A was individually added to primary cultures of rat anterior pituitary cells with no prior coincubation, rhFS288 failed to block the action of activin A. Similarly, inhibin A had to be added 3–4 h before activin A to be an effective antagonist. Otherwise, it was ineffective when added simultaneously with activin A. These observations imply that activin A can trigger cellular responses more rapidly than either follistatin or inhibin can exert their antagonistic function. This is consistent with the rapid kinetics of activin-induced oligomerization of type I and type II receptors (65) and Smad2 or Smad3 association with type IB or Alk-4 activin receptor (52).
One striking difference between Smad7 mRNA regulation in cultured rat
anterior pituitary and T3–1 or LT2 gonadotrope cells was
their differential responses to forskolin. Whereas forskolin had no
effect in primary pituitary cells, it increased Smad7 mRNA levels in
T3–1 cells and decreased them in LT2 cells. Forskolin may have
also altered Smad7 mRNA levels of primary gonadotropes, but this effect
would have been masked by the responses of other cell types. The effect
of forskolin in T3–1 or LT2 cells could reflect the activation
of different autocrine loops involving activins or other members of the
TGF family of growth factors. Alternatively, protein kinase A might
alter Smad7 expression by transcriptional mechanisms, by influencing
mRNA stability or by an indirect effect on Smad2/3-mediated mechanisms
that involve phosphorylation. Which of the cell lines, T3–1 or
LT2, reflects the mechanism of Smad7 mRNA regulation by
cAMP-dependent pathways in primary gonadotropes remains to be
determined. Unlike forskolin and in agreement with previous
observations (41), activation of the protein kinase C
pathway by either TPA or GnRH had no effect on Smad7 mRNA levels.
The modulation of pituitary function by the interaction of factors that
arise from central, peripheral, and local sources is quite complex.
Members of the TGF family of growth and differentiation factors such
as activins, inhibins, and TGF represent an important
autocrine/paracrine network within the pituitary (6).
There is compelling evidence that locally secreted follistatins and
inhibins are crucial modulators of the responses of gonadotropes, and
possibly other pituitary cell types, to activins. The results of the
present study indicate that the local tone of this extracellular
regulatory network is both regulated by and superimposed on
intracellular modulatory mechanisms dependent on molecules such as
Smad7. Activin controls both types of counterregulatory mechanisms, but
each responds with markedly different kinetics. For example, activin
promotes the inactivation of its own actions by stimulating pituitary
follistatin production (31). Activin also regulates Smad7
production, thereby terminating its own signaling cascade and thus
limiting follistatin production. Follistatin mRNA levels of rat
anterior pituitary cells increase almost linearly for 6 h after
activin A treatment (57), at which time Smad7 mRNA levels
have returned to almost baseline levels. Thus, Smad7 is important for
rapid inactivation of signaling, whereas follistatin plays a more
important role in the tonic control of activin signaling.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Medical and Molecular Genetics,
Indiana University School of Medicine, Indianapolis, Indiana 46202.
3 Senior Foundation for Medical Research Investigator.
Received October 5, 2000.
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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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 A. S. Dighe, F. J. Hayes, J. Khosravi, U. Bodani, and P. M. Sluss Comparison of Inhibin A Immunoassays: Recommendation for Adoption of Standardized Reporting Clin. Chem., April 1, 2004; 50(4): 767 - 769. [Full Text] [PDF]
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 K. A. Prendergast, L. L. Burger, K. W. Aylor, D. J. Haisenleder, A. C. Dalkin, and J. C. Marshall Pituitary Follistatin Gene Expression in Female Rats: Evidence That Inhibin Regulates Transcription Biol Reprod, February 1, 2004; 70(2): 364 - 370. [Abstract] [Full Text] [PDF]
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 L. M. Bilezikjian, A. M. O. Leal, A. L. Blount, A. Z. Corrigan, A. V. Turnbull, and W. W. Vale Rat Anterior Pituitary Folliculostellate Cells Are Targets of Interleukin-1{beta} and a Major Source of Intrapituitary Follistatin Endocrinology, February 1, 2003; 144(2): 732 - 740. [Abstract] [Full Text] [PDF]
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 C. Welt, Y. Sidis, H. Keutmann, and A. Schneyer Activins, Inhibins, and Follistatins: From Endocrinology to Signaling. A Paradigm for the New Millennium Experimental Biology and Medicine, October 1, 2002; 227(9): 724 - 752. [Abstract] [Full Text] [PDF]
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