| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
INTRACELLULAR SIGNAL SYSTEMS |
Institut National de la Santé et la Recherche Médicale, Unité 344, Endocrinologie Moléculaire, Faculté de Médecine Necker (F.D., E.S., P.A.K., M.E.), 75730 Paris, France; and Laboratoire de Physiologie Générale et Comparée (F.D., B.D.), Muséum National d’Histoire Naturelle, Unité Mixte de Recherche 8572 Centre National de la Recherche Scientifique, 75231 Paris cedex 05, France
Address all correspondence and requests for reprints to: Marc Edery, Institut National de la Santé et la Recherche Médicale, Unité 344, Faculté de Médecine Necker Enfants malades, 156 rue de Vaugirard, 75730 Paris Cedex 15, France. E-mail: marc.edery{at}necker.fr
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The PRL receptor (PRLR) belongs to the class I cytokine receptor superfamily that includes receptors for GH, erythropoietin (EPO), and most of the interleukins (1). PRL binding to its receptor induces receptor dimerization and activation of the associated kinase JAK2. This leads, in turn, to tyrosylphosphorylation of the PRLR and subsequently to transmission of the PRL signal and activation of milk-protein gene transcription. On PRLR/JAK2 activation, signal transducer and activator of transcription (STAT)5 rapidly undergoes tyrosylphosphorylation, leading to its homo- and/or heterodimerization and translocation to the nucleus, where it induces transcription of PRL-responsive genes such as ß-casein (2, 3).
There is abundant information on PRL-dependent signaling; however, much less is known about how PRL signal transduction is switched off (4, 5, 6).
The recently discovered suppressor of cytokine signaling (SOCS) family
of proteins has been implicated in the negative regulation of several
cytokine pathways, particularly those implicating receptor-associated
tyrosine kinases (7). The SOCS family consists of eight
proteins: SOCS1–SOCS7 and CIS [cytokine-inducible SH2-containing
protein]. Gene deletion studies in mice have demonstrated that SOCS-1
has a clear role in the negative regulation of interferon-
signaling
(8, 9). The analysis of mouse embryos lacking SOCS-3
suggests that it negatively regulates fetal liver erythropoiesis,
probably through its ability to modulate EPO signaling
(10). SOCS-2-deficient mice grew significantly larger than
their wild-type littermates, indicating a negative regulatory
role of SOCS-2 in the GH/IGF-I pathway. Interestingly, no phenotype
associated with PRL action has been reported in these knockout models
(11).
Structurally, SOCS proteins are composed of an N-terminal region of variable length and amino acid composition, a central SH2 domain, and a so-called SOCS box in the C-terminal region. Certain SOCS proteins have been implicated in the down-regulation of PRL-mediated signal transduction. Though both SOCS-1 and SOCS-3 negatively regulate PRL-mediated activation of the ß-casein gene promoter, they exert these effects through different mechanisms (5). SOCS-1 interacts with the catalytic region of the JAK2 tyrosine kinase domain (JH1) and suppresses tyrosine kinase activity and, as a result, the activation of STATs (4). Although SOCS-3 also binds to JAK2, it is not clear whether it can inhibit its tyrosine kinase activity (12, 13). Furthermore, in contrast to SOCS-1 and SOCS-3, SOCS-2 seems to restore PRL signal transduction at high concentrations, whereas it is a partial inhibitor of signal transduction at low concentrations. A striking similarity of phenotypes was found between CIS transgenic mice and STAT5 knockout mice. CIS transgenic mice exhibited growth retardation and defect in mammary gland development as well as in T cell and NK cell development. A decrease in STAT5 activation was observed in response to GH, PRL, and IL-2 in transgenic mice (14).
It is known that CIS binds specifically to phosphorylated tyrosines in the cytoplasmic tail of the GH receptor (GHR), in the absence of GH stimulation (15). Investigation of the latter mechanism revealed that CIS partially inhibits GHR-JAK2 signaling, an inhibition which is decreased at elevated STAT5b levels and may involve competition between CIS and STAT5b for common cytoplasmic tail phosphotyrosine-binding sites in the GHR. A second pathway has been described, involving a time-dependent inhibition, not seen with SOCS-1 or SOCS-3, that involves proteasome action in which GH stimulates degradation of CIS (16). Studies examining negative regulation of CIS have not been fully addressed in PRL signal transduction. Whereas SOCS-1, SOCS-2, and SOCS-3 inhibit PRL signaling, CIS was found to have no effect on the activation in 293 cells of PRL-responsive genes such as lactogenic hormone responsive element (LHRE)thymidine kinase (TK) promoter. This is a fusion gene carrying 6 copies of the LHRE and the TK minimal promoter linked to the coding region of the luciferase gene (the LHRE represents the STAT5 binding element of ß-casein promoter). To further our understanding of how CIS inhibits PRL signaling, we decided to study the effect of SOCS proteins using the -2300/+490 ß-casein promoter.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Expression plasmid DNA, pXM-MGF/STAT5a, encoding bovine MGF/STAT5a, was obtained from Dr. B. Groner (Freiburg, Germany). CMV ß-galactosidase cDNA was used as internal control to normalize ß-casein-luciferase expression in cell-transient transfection assays (17), and pcDNA3 vector (Promega Corp., Madison, WI) was used for DNA complementation. Ovine PRL (NDDK-oPRL-20) was a gift from the National Hormone and Pituitary/NIDDK Program (Baltimore, MD).
The antiphosphotyrosine antibody (
PY) and the anti-JAK2 antibody
(JAK2) were purchased from Upstate Biotechnology, Inc.,
Lake Placid, NY; and the polyclonal anti-mSTAT5a was from
Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). Anti-FLAG
monoclonal antibody is a product of Sigma (St. Louis,
MO).
Cell culture and transfections
The human embryonic kidney fibroblast HEK 293 cell line was used
for transient transfection and maintained in
DMEMnut F12 complemented with 10% FCS, 2
mM glutamine, and antibiotics.
Cells were split into six-well plates at a density of 800,000 cells per
well (
70% confluency) in DMEM (4.5 g/liter of glucose, 10% FCS, 2
mM glutamine, antibiotics) before being transiently
transfected using the calcium phosphate technique (19);
0.1 µg/well of wild-type ß-casein-luciferase plasmid, CMV
ß-galactosidase cDNA, and plasmids encoding STAT5a, 0.05 µg/well of
plasmid pRc/CMV containing PRLR cDNA and increasing
concentrations (0–250 ng DNA) of FLAG epitope-tagged SOCS-1,
SOCS-2, SOCS-3 or CIS (also referred as CIS-1) in pEF-BOS expression
vector (20) and pcDNA3 vector was used for DNA
complementation.
Within 15 h after transfection, cells were starved, in the absence of FCS, in DMEM (4.5 g/liter of glucose) for an additional 7 h of starvation. Cells were then stimulated for 10–12 h for functional test with oPRL (1 µg/ml). Luciferase activity was measured in relative light units and normalized by the estimated ß-galactosidase activity, as previously described (19). No induction of luciferase activity equals 0-fold induction. This means that luciferase activity in hormone-stimulated cells is identical to the one measured in nonstimulated cells. The actual ratio would be 1, but that has been normalized to 0 by withdrawing 1 from each individual value of fold induction. So, 0% is the real baseline, and all values above 0 are considered positive.
Whole cell extracts
HEK 293 cells were grown in a 100-mm culture dish. Transient
transfection was performed as above, using 2 µg cDNA encoding the
PRLR, 0.2 µg cDNA encoding the human tyrosine kinase JAK2, 1 µg
SOCS-1- and SOCS-3-encoding plasmids, and 4 µg CIS-encoding
plasmid.
After transfection cells were treated for15 min with oPRL (1 µg/ml), cells were washed with 1x PBS to remove media and serum, scraped, and collected in 1 ml of 1x PBS with 1 mM Na3Vo4. Cells were centrifuged at 900 x g at 4 C for 5 min and subsequently resuspended and lysed with 0.5 ml of lysis buffer containing a cocktail of protease inhibitors (1 mM phenylmethylsulfonylfluoride, 1 µg/ml pepstatin, 2 µg/ml leupeptin, 5 µg/ml aprotinin) for 30 min at 4 C. Extracts were centrifuged at 21,900 x g at 4 C for 10 min.
Immunoprecipitation and Western blotting
For immunoprecipitation, 500 µl of lysates were incubated with
1.25 µl anti-JAK2 antibody (1 µg/ml) and mixed with 25 µl Protein
A-Agarose (Santa Cruz Biotechnology, Inc., Santa
Cruz, CA), or anti-FLAG monoclonal antibody M2 for 2 h with
shaking. The immunoprecipitate was collected by centrifugation, washed
in lysis buffer (10 mM Tris-HCL, pH7.5; 5 EDTA; 150 NaCl;
30 sodium pyrophosphate; 50 NaF; 1 Na3VO4; 10%
glycerol; 0.5% Triton X-100), and boiled for 5 min in sample buffer
(125 mM Tris, pH 6.8; 5% SDS; 10% ß-mercaptoethanol;
20% glycerol).
Immunoprecipitated proteins were separated by SDS-PAGE, 7% for 2 h at 30 mA. Gel was transferred onto polyvinylidene difluoride transfer membranes (Polyscreen, NEN Life Science Products, Boston, MA) and immunodetected with appropriate antibodies to anti-JAK2 (1:1000), anti-FLAG (0.5 µg/ml), antiphosphotyrosine (1:10.000), and anti-PRLR (1 µg/ml) and visualized by enhanced chemiluminescence (Amersham Pharmacia Biotech, Arlington Heights, IL).
Experiments were repeated three times, and a representative blot is shown in each figure.
Western Blotting, using anti-FLAG monoclonal antibody M2, confirmed that increasing the concentration of transfected SOCS plasmids resulted in increased expression of SOCS proteins.
Quantification
Bands were scanned and analyzed with a DC 120 digital camera
coupled with 1D2.0.2 software (both from Eastman Kodak Co., Rochester, NY).
Statistical analysis
In each experiment, test values were compared with the control.
Data were subjected to ANOVA, and individual differences were tested
using the Fisher’s test. Statistically significant differences were
expressed as: *, P < 0.05; **, P <
0.01.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Luciferase activity, obtained in dose-response experiments, was
normalized and represented as maximal fold induction. Fold induction
represents the ratio of luciferase activity determined in the presence
or absence of PRL. Luciferase activity was assayed in cells transfected
without SOCS or several ratios of SOCS to PRLR cDNA. The values for
each experiment are expressed as a percentage of the control activity
(in the absence of transfected SOCS) that corresponds to 100%
(21). The constitutive expression of the SOCS-1 gene, at
increasing concentrations, led to inhibition of the activation of
transcriptional activity, even with very low doses of transfected SOCS
cDNA (Fig. 1A
). SOCS-3 constitutive
expression also blocked the ability of the PRLR to activate the
transcriptional response, but higher concentrations of transfected
plasmid were needed to obtain this effect (Fig. 1C). Whereas
overexpression of SOCS-2 at low concentrations gave an inhibition of
20%, compared with positive control samples, higher concentrations
actually resulted in a restoration and even a potentiation (200%-fold
induction, compared with controls) of the responsiveness of the
ßcasein construct to PRL (Fig. 1B).
|
, introducing SOCS-1 at a constant
amount, with increasing concentrations of SOCS-2, resulted in the
restoration of transcriptional activity in a dose-dependent manner,
compared with the positive control (PRL stimulation in the absence of
any SOCS plasmids). A similar study was conducted with a constant
amount of SOCS-3 and increasing concentrations of SOCS-2, resulting in
a restoration of 50% of transcriptional activity, compared with the
positive control (Fig. 2B).
|
), whereas, as previously reported, CIS
did not affect LHRE-TK promoter activation by PRL (Fig. 3B).
|
. As shown in Fig. 4, the
coexpression of SOCS-1 or SOCS-3 and CIS dramatically reduced
luciferase activity (Fig. 4, A and C), whereas coexpression of SOCS-2
and CIS had no inhibitory effects, as compared with our positive
control with low concentrations of SOCS-2; however, the higher
concentrations of SOCS-2 restored the transcriptional activity in a
dose-dependent manner (Fig. 4B).
|
).
However, constitutive expression of CIS plasmid did not affect JAK2
tyrosine kinase activity (Fig. 5).
|
. Within constitutive expression of
SOCS-1, a major band of 130-kDa coimmunoprecipitated with the anti-FLAG
antibody and was identified, as JAK2, by immunoblotting with an
antibody to JAK2. Although SOCS-1 was shown in Fig. 5 to greatly reduce
(but not completely suppress) tyrosine phosphorylation of JAK2, the
apparent level of tyrosine phosphorylation of JAK2 in Fig. 6 can be
attributed mainly to the use of the anti-FLAG antibody for
immunoprecipitation, which can coimmunoprecipitate
tyrosine-phosphorylated JAK2 through its recruitment to SOCS-1. When
SOCS-3 and CIS were expressed, a major band (92 kDa) was
coimmunoprecipitated with the anti-FLAG antibody. The PRLR monoclonal
antibody revealed 92-kDa proteins, indicating that SOCS-3 and CIS
associates with the PRLR that was tyrosine-phosphorylated (Fig. 7).
|
|
). In
contrast, overexpression of CIS resulted in inhibition of STAT5a
tyrosylphosphorylation. When the membrane was stripped and reprobed
with a STAT5a antibody, equal amounts of the immunoprecipitated STAT5a
were seen to be present in each condition (Fig. 8, middle
blot).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Though both SOCS-1 and SOCS-3 negatively regulate PRL-mediated activation of gene transcription, they exert these effects through different mechanisms (4, 5). Furthermore, SOCS-2 (in contrast with SOCS-1 and SOCS-3) has only partial inhibitory effects on PRL-mediated activation of the JAK/STAT pathway and PRL-dependent gene activation (4). With respect to CIS, different results have been reported, according to the PRL responsive promoter construct used. Indeed, we have reported previously that although CIS gene expression is induced by PRL, the constitutive expression of CIS does not affect PRL-induced transactivation of the LHRE-TK promoter (4, 6).
However, a number of studies have reported CIS-dependent
down-regulation of cytokine signaling (8, 22, 23). We
chose to re-examine CIS action on PRL signaling, using a more
physiological construct (the ß-casein promoter). Our first set of
experiments show that CIS inhibits, by up to 70%, PRL-induced
activation of transcriptional activity. To examine the interaction of
CIS with SOCS-1, SOCS-3, and SOCS-2, we established that both SOCS-1
and SOCS-3 also negatively regulate PRL-mediated activation of the
ß-casein gene promoter. Moreover, the coexpression of CIS with SOCS-1
or SOCS-3, at increasing concentrations, resulted in a dramatically
reduced transcriptional activity, suggesting a cooperative effect of
the two SOCSs. However, constitutive expression of CIS and SOCS-2 at
increasing concentrations resulted in a dose-dependent restoration of
the transactivation of transcription and even to an amplification
(150%) of the maximal activation obtained in the absence of SOCS gene
expression. Another feature associated with SOCS-2 action was its
capacity to abrogate transcriptional inhibition induced by SOCS-1,
SOCS-3, and CIS. The results indicate that SOCS-2 seems to be an
antagonist of other SOCSs. Interestingly, the restoration of SOCS-3
inhibited-transcription was not observed in the PRL-induced
transactivation via the LHRE-TK promoter or GH-induced transactivation
of LHRE-TK promoter (4, 24). In the present experiments,
we used the wild-type ß-casein promoter, which represents the
endogenous regulatory system that implicates several factors, including
STAT5. This contrasts to the LHRE promoter, which is simply a
multimer of the STAT5-responsive element. The differences
between the present observations and those obtained with the
LHRE-promoter may thus result from the integration of input from other
transcription factors on the wild-type ß-casein promoter. The effect
of SOCS-2 on GH signaling has also been shown to be dose-dependent.
SOCS-2-deficient mice display gigantism, indicating a key physiological
role for SOCS-2 in the control of postnatal growth by GH/IGF-I
(11, 25). Yet, an inhibitory action of SOCS-2 on GH
signaling was observed only at low concentrations (24).
Although SOCS-2 is a negative regulator of signaling for
growth-promoting cytokines (11), the inhibitory response
of SOCS-2, on PRLR-induced ß-casein gene promoter activation, seen
here was absent. However, the results indicate that SOCS-2 can play
both a permissive and a potentiator role in PRL-signaling. Indeed, low
doses of SOCS-2 result in a modest inhibitory effect; probably this
effect was a result of endogenous SOCS action (data not shown);
whereas, at higher concentrations of transfected SOCS-2 plasmid, a
characteristic effect of SOCS-2 is observed, featuring a dose-related
potentiation of transcription, reaching even superinduction (200%) of
the maximal activation obtained in the absence of constitutive
expression of SOCS genes. These findings suggest that a major action of
SOCS-2 is to restore the sensitivity to PRL by overcoming the initial
inhibitory effects of other endogenous SOCS molecules. Other authors
have reported only partial (or absence of) inhibitory effect of SOCS-2
in regulating gene activation in response to PRL (6), GH
(16, 26), and IL-4 (27). What is the
mechanism involved in CIS inhibition of PRL signaling? The PRLR itself
is a substrate for the JAK2 kinase and is critical for biological
activity (28). To examine the role of CIS protein in
PRL-induced JAK2 tyrosylphosphorylation, we transiently coexpressed the
PRLR alone or in combination with FLAG-tagged SOCS-1, SOCS-3, and CIS.
No change in tyrosylphosphorylation of JAK2 was observed when
overexpressing CIS, whereas SOCS-1 reduced tyrosylphosphorylation of
JAK 2 as a result of SOCS-1/JAK2 complex formation (Figs. 5 and 6)
(4, 5). Based on these results, it seems that CIS inhibits
PRLR signaling by a distinct mechanism from that documented for SOCS-1,
and that this inhibition occurs downstream of JAK2.
We next examined whether CIS protein could interact with the PRLR. A
precedent for this possibility was provided by the report that CIS
seems to negatively regulate cytokine signaling by competition with
STAT5 for binding to phosphotyrosine residues within the erythropoietin
and IL-3 receptor cytoplasmic domains (22, 23, 29).
Western blot analyses of proteins coimmunoprecipitating with anti-FLAG
antibodies showed that CIS bound to the PRLR. The PRRL is
tyrosine-phosphorylated in the absence of PRL stimulation because, in
our system, there is more of JAK2 cotransfected; and it is known that
the tyrosine kinase activity of JAK2 is possible in the absence of
stimulation (Fig. 7). The same result was obtained with SOCS-3. This is
consistent with previous reports indicating that SOCS3- and CIS
binding requires tyrosine-phosphorylated GHR, whereas SOCS-1 binding is
tyrosine-phosphorylation-independent (15, 26). It is known
that SOCS-3 interacts with several tyrosine-phosphorylated receptors,
such as gp130 in IL-6 signaling (30, 31), the EPO receptor
(32), and the IGF-I receptor (33).
Interestingly, the inhibitory actions of CIS, via direct binding to the
PRLR described here, have also been observed for CIS inhibition of GHR
signaling via GHR interaction (14, 15). Interplay between
CIS and PRL signaling is further complicated by the fact that CIS is
induced by STAT5, which, in turn, inhibits STAT5 function (23, 34, 35, 36). In CIS transgenic mice, there is both a significant
decrease in ß-casein protein levels and an inhibition of STAT5
activation in response to PRL. The phenotypes are strikingly similar to
those of STAT5a and/or STAT5b knockout mice (14). Because
STAT5 is tyrosine phosphorylated in response to PRL and is necessary
for transmission of the PRL signal, we examined the role of the CIS
protein in regulating PRL-induced activation of STAT5. We clearly
demonstrate an inhibition of STAT5a tyrosylphosphorylation, a finding
that is consistent with the very low tyrosylphosphorylation of STAT5
seen in CIS transgenic mice.
CIS protein has been shown to associate with the tyrosine-phosphorylated GH, EPO, and IL-3 receptors (16, 22, 37). It was recently found that CIS protein could also bind to the IL-2-receptor ß-chain, but not to gp 130, a signal-transducing subunit of the IL-6-receptor.
Selective binding of CIS to receptors, which activate STAT5, may explain the selective negative effect of CIS on STAT5 activation. However, the molecular mechanism of STAT5 inhibition by CIS has not yet been clarified. It is known that CIS binds to the region of the EPO receptor containing the second tyrosine residue (Y401) (37). One of the potential mechanisms could be the masking of the STAT5 binding sites on the receptor by a competition between CIS and STAT5 binding sites. Such a model is supported by the observation that when STAT5 is overexpressed, the negative effect of CIS can be counteracted (14, 16, 38). Another possibility is that CIS accelerates the degradation of the receptor-CIS complex by the ubiquitin-proteasome pathway (16, 37, 38), although this remains to be confirmed within the PRLR system. We still have no clear explanation why we and others cannot find any inhibitory effect of CIS on LHRE luciferase activity. As we suggested, one possibility could be attributed to different transfection conditions used with the ß-casein luciferase construct, or that other factors, corespressors, or coactivators are involved in this inhibition, which are effective only on the promoter construct of the ß-casein but not the STAT5 construct. This may involve a step distal from receptor phosphorylation not involving STAT5 or not depending on the putative importance of cofactors (repressors or activators) in their association with STAT5 and subsequent effects on CIS inhibition on signaling.
In conclusion, the present results demonstrate that SOCS-1, SOCS-2, SOCS-3, and CIS inhibit PRL signaling by multiple mechanisms involving either association to the JAK2 kinase or to the PRLR. Detailed studies of multiple SOCS/CIS-deficient mice should provide further insight into which PRL signaling steps and physiological responses are regulated by each PRL-inducible CIS/SOCS protein.
|
Footnotes |
|---|
Received May 24, 2001.
Accepted for publication August 28, 2001.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
signaling and prevents the
potentially fatal neonatal actions of this cytokine. Cell 98:597–608[CrossRef][Medline]
This article has been cited by other articles:
 |
|
 |
|
  J. Piessevaux, D. Lavens, T. Montoye, J. Wauman, D. Catteeuw, J. Vandekerckhove, D. Belsham, F. Peelman, and J. Tavernier Functional Cross-modulation between SOCS Proteins Can Stimulate Cytokine Signaling J. Biol. Chem., November 3, 2006; 281(44): 32953 - 32966. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Anderson, P. Beijer, A. S. Bang, M. A. Fenwick, S. J. Bunn, and D. R. Grattan Suppression of Prolactin-Induced Signal Transducer and Activator of Transcription 5b Signaling and Induction of Suppressors of Cytokine Signaling Messenger Ribonucleic Acid in the Hypothalamic Arcuate Nucleus of the Rat during Late Pregnancy and Lactation Endocrinology, October 1, 2006; 147(10): 4996 - 5005. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. T. Anderson, J. L. Barclay, K. J. Fanning, D. H. L. Kusters, M. J. Waters, and J. D. Curlewis Mechanisms Underlying the Diminished Sensitivity to Prolactin Negative Feedback during Lactation: Reduced STAT5 Signaling and Up-Regulation of Cytokine-Inducible SH2 Domain-Containing Protein (CIS) Expression in Tuberoinfundibular Dopaminergic Neurons Endocrinology, March 1, 2006; 147(3): 1195 - 1202. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Tannahill, J. Elliott, A. C. Barry, L. Hibbert, N. A. Cacalano, and J. A. Johnston SOCS2 Can Enhance Interleukin-2 (IL-2) and IL-3 Signaling by Accelerating SOCS3 Degradation Mol. Cell. Biol., October 15, 2005; 25(20): 9115 - 9126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Lindberg, S G Ronn, D Tornehave, H Richter, J A Hansen, J Romer, M Jackerott, and N Billestrup Regulation of pancreatic {beta}-cell mass and proliferation by SOCS-3 J. Mol. Endocrinol., October 1, 2005; 35(2): 231 - 243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. C. Brelje, L. E. Stout, N. V. Bhagroo, and R. L. Sorenson Distinctive Roles for Prolactin and Growth Hormone in the Activation of Signal Transducer and Activator of Transcription 5 in Pancreatic Islets of Langerhans Endocrinology, September 1, 2004; 145(9): 4162 - 4175. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Zoubiane, A. Valentijn, E. T. Lowe, N. Akhtar, S. Bagley, A. P. Gilmore, and C. H. Streuli A role for the cytoskeleton in prolactin-dependent mammary epithelial cell differentiation J. Cell Sci., January 15, 2004; 117(2): 271 - 280. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Endo, A. Sasaki, M. Minoguchi, A. Joo, and A. Yoshimura CIS1 Interacts with the Y532 of the Prolactin Receptor and Suppresses Prolactin-Dependent STAT5 Activation J. Biochem., January 1, 2003; 133(1): 109 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Greenhalgh, D. Metcalf, A. L. Thaus, J. E. Corbin, R. Uren, P. O. Morgan, L. J. Fabri, J.-G. Zhang, H. M. Martin, T. A. Willson, et al. Biological Evidence That SOCS-2 Can Act Either as an Enhancer or Suppressor of Growth Hormone Signaling J. Biol. Chem., October 18, 2002; 277(43): 40181 - 40184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Curlewis, S. P. Tam, P. Lau, D. H. L. Kusters, J. L. Barclay, S. T. Anderson, and M. J. Waters A Prostaglandin F2{alpha} Analog Induces Suppressors of Cytokine Signaling-3 Expression in the Corpus Luteum of the Pregnant Rat: A Potential New Mechanism in Luteolysis Endocrinology, October 1, 2002; 143(10): 3984 - 3993. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
