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(IFN) Regulation of IFN-Stimulated Gene Expression in Cell Lines Lacking Specific IFN-Signaling Components1
Center for Animal Biotechnology and Genomics, Department of Animal Science, Texas A&M University, College Station, Texas 77843-2471
Address all correspondence and requests for reprints to: Thomas E. Spencer, Center for Animal Biotechnology and Genomics, 442 Kleberg Center, 2471 TAMU, Texas A&M University, College Station, Texas 77843-2471. E-mail: tspencer{at}ansc.tamu.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(IFN) is a unique type I IFN secreted by the ruminant
conceptus that acts in a paracrine manner on the endometrial epithelium
to signal pregnancy recognition. In the ovine endometrium, IFN
suppresses estrogen receptor 
and oxytocin receptor gene expression,
but increases or induces expression of IFN-simulated genes (ISGs),
including signal transducer and activator of transcription-1 (STAT1),
STAT2, ISG factor-3
(ISGF3)/p48/IFN regulatory factor-9, and
2',5'-oligoadenylate synthetase (OAS). Human fibroblast cell lines
lacking specific IFN signaling components were employed to determine
the roles of STAT1, STAT2, and ISGF3 in the effects of IFN on ISG
protein expression. Results indicated that STAT1 or STAT1ß is
required for IFN effects on STAT2, ISGF3, and OAS (40/46, 69/71,
and 100 kDa). STAT2 is required for effects on STAT1, ISGF3, and all
OAS forms. ISGF3 is required for effects of IFN on STAT2 and
40/46- and 69/71-kDa OAS and plays a role in the effects of IFN on
100-kDa OAS and STAT1. Mutation of Tyr701, but not
Ser727, of STAT1 abolished the effects of IFN on ISG
expression. Mutation of the SH2 domain of STAT1 abolished the effects
of IFN on all ISGs and reduced increases in 100-kDa OAS. These data
illustrate the importance of transcription factors composed of STAT1,
STAT2, and ISGF3 in the signaling pathway mediating the effects of
IFN on ISG expression. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(IFN), the
pregnancy recognition signal in ruminants, is secreted by trophectoderm
of ovine conceptuses (embryo and associated membranes) between days 11
and 23 of pregnancy (1). IFN is a unique member of the
type I IFN family and possesses antiviral, antiproliferative, and
immunomodulatory activities similar to those of other type I IFNs
(2, 3, 4, 5). IFN binds to classical type I IFN receptors in
the ovine endometrium (6) to prevent uterine release of
luteolytic pulses of PGF2 from the endometrial
luminal epithelium (LE) and superficial glandular epithelium (GE)
(7, 8). Available evidence indicates that IFN inhibits
transcription of estrogen receptor and oxytocin receptor genes to
block development of the uterine luteolytic mechanism (9, 10).
In addition to negative effects on gene expression, IFN increases or
induces the expression of a number of IFN-stimulated genes (ISGs) in
the endometrial stroma and GE. In the ovine endometrium in
vivo or endometrial cells in vitro, IFN induces or
increases the expression of signal transducer and activator of
transcription-1 (STAT1) and -2 (11, 12),
ß-microglobulin (13), IFN regulatory factor-1
(IRF-1) (10, 11, 12), ubiquitin cross-reactive protein [UCRP;
also known as IFN-stimulated gene 17 (ISG17)] (11, 12, 14, 15), Mx (16), and 2',5'-oligoadenylate synthetase
(OAS) (17, 18). In the endometrium of early pregnant or
cyclic ewes receiving intrauterine injections of recombinant ovine
IFN, these ISGs are specifically up-regulated in the stroma and GE
(14, 18). The precise role of these proteins and the
cellular and molecular mechanism(s) by which IFN regulates increases
in their expression are not known.
The results of recent studies indicate that IFN activates a signal
transduction pathway similar to that of IFN/ß in an ovine
endometrial LE cell line (11, 12). Within 30 min of IFN
stimulation, STAT1, -2, -3, -5a/b, and -6 become phosphorylated on
tyrosine and translocate to the nucleus. However, in response to
stimulation with IFN for more than 30 min, STAT1 and -2 remain
tyrosine phosphorylated, whereas STAT3, -5a/b, and -6 are rapidly
dephosphorylated. IFN induces formation of STAT1 homodimers
[-activated factor (GAF)], as well as IFN-stimulated gene factor-3
(ISGF3), which is composed of STAT1, STAT2, and ISGF3
(12). GAF regulates transcription through -activated
sequence (GAS) elements in the promoter region of many ISGs such as
IRF-1 (19). ISGF3 binds to IFN-stimulated response
elements (ISREs) to drive transcription of ISGs such as UCRP
(20) and OAS (21). The precise roles of ISGF3
and GAF in the activation of ISGs by IFN have not been
investigated.
This study tested the hypotheses that 1) ISGF3 mediates positive
effects of IFN on ISG expression; 2) STAT1 tyrosine phosphorylation,
serine phosphorylation, and Src homology 2 (SH2) domain are required
for effects of IFN on ISG expression; and 3) STAT1ß is sufficient
to mediate the effects of IFN on ISG expression. To test these
hypotheses, we determined the effects of IFN on STAT1, STAT2,
ISGF3, and OAS protein expression in human fibroblast cell lines
deficient in STAT1/ß, STAT2, or ISGF3 or STAT1-deficient cells
complemented with various mutants of STAT1
(Tyr701, Ser727, SH2, and
STAT1ß/p84).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. The 2fTGH cells were maintained in
basal medium containing DMEM with F-12 salts (DMEM-F12;
Sigma-Aldrich Corp., St. Louis, MO) supplemented with 10%
FBS and penicillin/streptomycin/amphotericin solution
(Life Technologies, Inc., Gaithersburg, MD). The U2A, U3A,
and U6A cells were maintained in basal medium with hygromycin B (250
µg/ml; Sigma-Aldrich Corp.). The U3A-701, U3A-727,
U3A-SH2, U3A-p84, and U3A-p91 cells were maintained in basal medium
with hygromycin B and G418 sulfate (400 µg/ml; Geneticin, Life Technologies, Inc.). Recombinant ovine IFN was prepared and
assayed for biological activity as described previously
(25).
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(I29320) from
Transduction Laboratories (Lexington, KY); rabbit anti-STAT2
(sc-476) from Santa Cruz Biotechnology, Inc. (Santa
Cruz, CA); rabbit antihuman OAS (26); and
peroxidase-conjugated goat antirabbit and antimouse IgG
(Kirkegaard & Perry Laboratories, Gaithersburg, MD).
Western blot analysis
Monolayer cultures were grown in culture medium to 80%
confluence on 100-mm tissue culture plates. Cells were then left
untreated as a control or treated with recombinant ovine IFN
(104 antiviral units/ml) for 1, 3, 6, 12, 24, or
48 h. This design was replicated in three independent
experiments.
To harvest total cellular protein for Western blot analyses, cells were then rinsed with cold Hanks’ Balanced Salt Solution and lysed by incubation in immunoprecipitation lysis buffer (1% Triton X-100, 0.5% Nonidet P-40, 150 mM NaCl, 10 mM Tris, 1 mM EDTA, 1 mM EGTA, 0.2 mM Na3VO4, 0.2 mM phenylmethylsulfonylfluoride, 50 mM NaF, 30 mM Na4P2O7, 1 µg/ml leupeptin, and 1 µg/ml pepstatin) for 30 min at 4 C. Cell lysates were passed through a 26-gauge needle and then clarified by centrifugation (16,000 x g, 15 min, 4 C). The protein concentration of the supernatant was determined by Bradford assay (Bio-Rad Laboratories, Inc., Hercules, CA) using BSA as the standard. Twenty micrograms of whole cell extract protein from each sample were separated by 10% SDS-PAGE and transferred to nitrocellulose as described previously (11). Blots were blocked for 1 h at room temperature with 5% (wt/vol) nonfat milk-TBST (Tris-buffered saline and 0.1% Tween-20). Primary antibodies were diluted according to the manufacturer’s recommendations in 2% milk-TBST. The OAS antibody was used at a 1:1000 dilution. Blots were incubated with primary antibody overnight at 4 C, rinsed for 30 min at room temperature with TBST, incubated with the appropriate peroxidase-conjugated secondary antibody for 1 h at room temperature, and then rinsed again for 30 min at room temperature with TBST. Immunoreactive proteins were detected by chemiluminescence (SuperSignal West Pico, Pierce Chemical Co., Rockford, IL) according to the manufacturer’s recommendations using X-OMAT AR x-ray film (Eastman Kodak Co., Rochester, NY). Multiple exposures of each Western blot were performed to ensure linearity of chemiluminescent signals. Western blots were quantified by scanning densitometry using a GS-690 Imaging Densitometer and MultiAnalyst software (Bio-Rad Laboratories, Inc., Hercules, CA).
Statistical analysis
Integrated optical density measurements were subjected to least
squares ANOVA using the General Linear Models procedures of Statistical
Analysis System version 8.1 for Windows (SAS Institute, Inc., Cary, NC). The model used in the least squares ANOVA
included time (hour post-IFN treatment) and replicate as sources of
variation. The initial measurement of band optical density at time zero
was used as a covariate. For analyses of U3A (STAT1-deficient)
complement cell lines, the STAT1 data were also used as a covariate.
The least square means (LSM) and SE illustrated in
scatterplot graphs were derived from this analysis. P
< 0.05 was considered statistically significant. If an effect of
IFN was detected, the data for each individual protein were then
analyzed by least squares regression analysis. In these analyses, time
was considered a continuous independent source of variation, with
replicate as a dependent source. The initial measurement of band
optical density at time zero was used as a covariate. For analyses of
U3A (STAT1-deficient) complement cell lines, the STAT1 data were also
used as a covariate to increase the fit of the regression.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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on ISG expression in parental (2fTGH)
fibroblasts), IFN increased the expression of
STAT1/ß, STAT2, ISGF3, and all forms of OAS. STAT1 and -2
were present at 0 h and increased in response to IFN
(quadratic; P < 0.001; r2 = 0.89
and 0.80, respectively). IFN induced STAT1ß protein by 12 h
of treatment. ISGF3 was induced between 3 and 6 h of IFN
treatment, and expression decreased between 24 and 48 h
(quadratic; P < 0.001; r2 =
0.79). IFN treatment did not affect (P = 0.60) the
expression of STAT3 protein.
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treatment (quadratic; P < 0.001;
r2 = 0.90). The 69/71-kDa OAS proteins were
induced between 3 and 6 h of IFN treatment, and 40/46-kDa OAS
proteins were induced between 6 and 12 h (quadratic;
P < 0.001; r2 = 0.78 and 0.82,
respectively).
Effects of IFN on ISG expression in fibroblasts lacking IFN
signaling components
In ISGF3-deficient U2A fibroblasts (Fig. 2), IFN did not increase the
expression of STAT2 (P = 0.62) or STAT3
(P = 0.39), or induce the expression of 40/46- and
69/71-kDa OAS (P = 0.79 and 0.36, respectively). IFN
increased the expression of STAT1 protein (linear; P <
0.001; r2 = 0.59) and 100-kDa OAS (linear;
P < 0.001; r2 = 0.64). However,
the magnitude of the increase was much lower in the ISGF3-deficient
U2A cells compared with the 2fTGH cells (
2- vs.
10-fold). The band with an apparent molecular mass less than 100 kDa
is probably a degradation product of the 100-kDa OAS protein.
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), IFN did not increase the
expression of STAT1/ß (P = 0.64), STAT3
(P = 0.45), or 100-kDa OAS (P = 0.30)
or the induce expression of ISGF3 (P = 0.38),
40/46-kDa OAS (P = 0.53), or 69/71-kDa OAS
(P = 0.99).
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), IFN did not increase the
expression of STAT2 (P = 0.66), STAT3
(P = 0.75), or 100-kDa OAS (P = 0.13)
proteins or induce the expression of ISGF3 (P =
0.27), 40/46-kDa OAS (P = 0.51), or 69/71-kDa OAS
(P = 0.53) proteins.
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on ISG expression in STAT1-deficient cells
complemented with STAT1, STAT1ß, or a specific STAT1 mutant/ß-deficient U3A cells have been
complemented with STAT1 (p91). The response of the U3A-p91 cells to
IFN was similar to that of the 2fTGH cells in terms of ISG
expression, except for the 100-kDa OAS form (Fig. 5). STAT2 was present at 0 h and
increased in response to IFN (quadratic; P = 0.001;
r2 = 0.81). ISGF3 was induced between 3 and
6 h of IFN treatment, and expression decreased between 24 and
48 h (quadratic; P < 0.006;
r2 = 0.68). The 100-kDa form of OAS was expressed
at 0 h and increased with IFN treatment (linear;
P < 0.001; r2 = 0.88). The
69/71- and 40/46-kDa OAS proteins were induced between 3 and 6 h
of IFN treatment (quadratic; P = 0.03;
r2 = 0.91 and 0.83, respectively).
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/ß-deficient U3A cells have been
complemented with a Y701F mutant of STAT1 (Fig. 6). IFN did not increase the
expression of STAT2 (P = 0.95), STAT3
(P = 0.70), or 100-kDa OAS (P = 0.65)
or induce the expression of ISGF3 (P = 0.35),
40/46-kDa OAS (P = 0.93), or 69/71-kDa OAS
(P = 0.78).
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/ß-deficient U3A cells have been
complemented with a R602L mutant of STAT1 (Fig. 7). IFN did not increase the
expression of STAT2 (P = 0.95) or induce the expression
of ISGF3 (P = 0.47), 69/71-kDa OAS
(P = 0.26), or 40/46-kDa OAS (P =
0.78). In contrast to U3A-701 cells, IFN increased STAT3 and 100-kDa
OAS (quadratic; P = 0.005 and 0.001;
r2 = 0.80 and 0.82, respectively). However, the
increase in 100-kDa OAS in U3A-SH2 cells was much lower than that in
2fTGH or U3A-p91 cells (2.5- vs. 10-fold). The
multiple immunoreactive proteins observed in the OAS blot are probably
breakdown products of the OAS protein that are evident due to increased
exposure length for determination of 100-kDa OAS expression.
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/ß-deficient U3A cells have been
complemented with a S727A mutant of STAT1 (Fig. 8). IFN increased the expression of
STAT2 (quadratic; P < 0.001; r2
= 0.87) and 100-kDa OAS (quadratic; P < 0.001;
r2 = 0.93). IFN induced the expression of
ISGF3, 69/71-kDa OAS, and 40/46-kDa OAS (quadratic;
P = 0.006, < 0.001, and < 0.001;
r2 = 0.75, 0.90, and 0.84, respectively) in a
manner similar to that observed for 2fTGH cells. IFN treatment
did not affect the expression of STAT3 protein (P =
0.29).
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), the
STAT1/ß-deficient U3A cells have been complemented with STAT1ß
(p84). STAT1ß is a naturally occurring splice variant of STAT1 and is
less transcriptionally active due to a truncated carboxyl-terminus
trans-activation domain (27). IFN increased
the expression of STAT2 (quadratic; P < 0.001;
r2 = 0.87), 100-kDa OAS (quadratic;
P = 0.003; r2 = 0.89), and STAT3
(quadratic; P < 0.001; r2 =
0.85). IFN induced the expression of ISGF3 (quadratic;
P < 0.006; r2 = 0.90), 69/71-kDa
OAS (quadratic; P < 0.003; r2 =
0.87), and 40/46-kDa OAS (linear; P < 0.001;
r2 = 0.83).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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activates an intracellular signaling pathway that is similar to other
type I IFNs (11, 12). In recent studies using ovine
endometrial cells (11, 12, 18), IFN stimulated the
formation of both ISGF3 and GAF complexes and increased or induced the
expression of STAT1, STAT2, UCRP, and all five OAS forms. Collectively,
the results presented here indicate that ISGF3 mediates the effects of
IFN on the expression of genes for STAT2, 69/71-kDa OAS, and
40/46-kDa OAS, whereas GAF, comprised of STAT1 and STAT2 heterodimers,
regulates the expression of the gene encoding the 100-kDa form of OAS.
However, both ISGF3 and GAF regulate the expression of the STAT1
gene.
In 2fTGH cells, IFN stimulated the expression of STAT1/ß,
STAT2, and 100-kDa OAS and induced the expression of ISGF3,
69/71-kDa OAS, and 40/46-kDa OAS. These results are similar to those
demonstrating that type I IFN and IFNß increase the expression of
STAT1, STAT2, ISGF3, and OAS (28, 29). Both type I and
II IFNs increase the expression of STAT1, whereas only type I IFNs
increase the expression of ISGF3, 69/71-kDa OAS (29).
Three major forms of OAS have been described in IFN-treated human
cells, corresponding to proteins of 40/46, 69/71, and 100 kDa
(26, 30, 31, 32). Each of the three major OAS forms are
encoded by separate genes and exhibit different biochemical
characteristics, subcellular localization, and regulatory responses
(33, 34, 35, 36, 37). Although IFN/ß induces the expression of
all forms of OAS, differential expression and induction of the various
OAS forms by each IFN has been observed in some cells (26, 31, 32, 34, 35, 36, 37). Therefore, it is not surprising that IFN
regulation of OAS gene expression is also complex. In this study IFN
increased the 100-kDa form of OAS, but induced the 69/71- and 40/46-kDa
isoforms of OAS. These results are reinforced by data showing that
IFN induces the 40/46- and 69/71-kDa OAS forms in ovine endometrial
stromal and GE cells, but only the 40/46-kDa OAS in LE
(18).
In fibroblasts lacking ISGF3 (U2A), IFN was unable to increase
the expression of STAT2 or induce 40/46-kDa OAS and 69/71-kDa OAS.
Likewise, in STAT2-deficient U6A cells, IFN did not increase STAT1
expression or induce ISGF3, 40/46-kDa OAS, and 69/71-kDa OAS
expression. In STAT1-deficient U3A cells, IFN was also unable to
stimulate the expression of STAT2 or induce ISGF3, 40/46-kDa OAS, or
69/71-kDa OAS. Collectively, these results support the idea that ISGF3
is required for IFN stimulation of genes for STAT2 and the 69/71-
and 40/46-kDa isoforms of OAS. Both type I and II IFNs increase the
expression of ISGF3 (29). ISGF3 was induced in 2fTGH
cells, but not in U3A or U6A cells, indicating that IFN-induced
ISGF3 expression is dependent on both STAT1 and STAT2. As U2A cells
lack ISGF3, we could not determine whether ISGF3 protein plays a
role in ISGF3 gene regulation. A linear increase in STAT1 protein
was observed in IFN-treated U2A cells; however, the magnitude of the
increase was much lower than that observed in 2fTGH parental cells.
These results suggest that IFN regulates STAT1 expression through
both ISGF3-dependent and ISGF3-independent mechanisms.
ISGF3-independent expression of STAT1 in response to IFN is
probably mediated by GAF, because STAT1 was not increased in U3A-701 or
U3A-SH2 cells treated with IFN. ISGF3-dependent expression of STAT1
in response to IFN can be inferred from the differential response of
2fTGH compared with U2A cells.
The differences observed in IFN regulation of 100-kDa OAS compared
with the 40/46- and 69/71-kDa OAS isoforms are a novel finding of this
study. The 100-kDa OAS form was expressed in unstimulated cells and
increased in IFN-treated ISGF3-deficient U2A cells. The
expression of 100-kDa OAS was not affected by IFN in STAT1-deficient
U3A cells or STAT2-deficient U6A cells, but was increased in U3A
cells complemented with either STAT1 or STAT1ß. In U3A-SH2 cells,
STAT1–2 heterodimers can form, because the SH2 domain of STAT2 is
sufficient for heterodimer formation (38). In contrast,
active STAT1–2 heterodimers cannot form in U3A-701 cells, because
tyrosine-phosphorylated STAT1 is required for nuclear translocation and
DNA binding (39, 40). Our results indicate that IFN
increases the expression of 100-kDa OAS via STAT1–2 heterodimers,
because 100-kDa OAS was increased in U3A-SH2 cells, but not in U3A-701
cells. Indeed, the 5'-flanking promoter/enhancer region of the 100-kDa
OAS gene contains five predicted GAS elements (37).
The inability of IFN to stimulate the expression of ISGs in the
STAT1-deficient U3A cells demonstrates the central role of this
transcription factor in the IFN signal transduction pathway. STAT1
has been demonstrated to be a major transcription factor in both type I
and type II IFN signal transduction pathways (41).
Interestingly, constitutive expression of several genes requires
unphosphorylated STAT1 (42). In this study STAT2, STAT3,
and 100-kDa OAS were constitutively expressed in STAT1-deficient U3A
cells at comparable levels to 2fTGH parental cells, indicating that
unphosphorylated STAT1 is not necessary for basal expression of these
genes. However, tyrosine phosphorylation of STAT1 is required for
effects of IFN on ISG expression.
Both type I and type II IFNs stimulate gene expression through the
phosphorylation of STAT1 by Janus kinases at the cell membrane
(41, 43). Phosphorylated STAT1 then homodimerizes,
translocates to the nucleus, and binds to GAS elements.
Homodimerization of STAT1 is mediated by binding of the phosphorylated
Tyr701 of one STAT1 monomer to the SH2 domain of
another (44). In mutant Tyr701 STAT1
fibroblasts (U3A-701), IFN did not affect the expression of ISGs.
Although STAT1 can associate with STAT2 without tyrosine
phosphorylation, tyrosine phosphorylation is required for strong
heterodimer formation, nuclear translocation, and DNA binding
(43). Therefore, tyrosine phosphorylation of STAT1 in
response to IFN is critical for IFN stimulation of target genes
controlled by ISGF3 and GAF. The SH2 domain of STAT1 mediates binding
of STAT1 to other tyrosine-phosphorylated STATs, such as STAT1 and
STAT2 (45). In STAT1 SH2 mutant fibroblasts (U3A-SH2),
IFN did not affect the expression of STAT2, ISGF3, or 69/71- or
40/46-kDa OAS isoforms, but did increase the expression of STAT3 and
100-kDa OAS. Therefore, STAT1 must associate with STAT1 and/or STAT2
via its SH2 domain to affect the transcription of STAT2, ISGF3,
40/46-kDa OAS, and 69/71-kDa OAS, but not to affect the transcription
of STAT3 and 100-kDa OAS.
Phosphorylation of STAT1 on Ser727 enhances
trans-activational capacity (46) and is
required for IFN induction of genes such as the double stranded,
RNA-dependent kinase PKR (47). In the present study
U3A-727, 2fTGH, and STAT1-complemented U3A cells responded similarly
to IFN treatment with increases in the expression of STAT2 and
100-kDa OAS and by inducing ISGF3, 69/71-kDa OAS, and 40/46-kDa OAS.
Therefore, serine phosphorylation of STAT1 does not appear to be
required for IFN stimulation of these ISGs.
STAT1ß (p84) lacks the 38 carboxyl-terminal amino acids of STAT1
and has been considered a less potent trans-activator than
STAT1 (27). However, STAT1ß can associate with STAT2
and ISGF3 to form ISGF3 (48). Results from the present
study indicate that STAT1ß can fully substitute for STAT1 in
regulating ISG expression in response to IFN. The effects of IFN
on the expression of STAT2, ISGF3, and OAS in U3A-p84 fibroblasts
were not different from those observed in 2fTGH cells.
The results of this study demonstrate the utility of these human
fibroblast cell lines for determining the cellular and molecular
mechanisms that mediate the effects of IFN on target gene
expression. During early pregnancy in sheep, IFN increases or
induces the expression of a number of ISGs (STAT1, STAT2, OAS, IRF-1,
ß2-microglobulin, Mx, and UCRP) in the
endometrium. The available results indicate that the effects of IFN
on the expression of STAT2, 40/46-kDa OAS, and 69/71-kDa OAS are
dependent on ISGF3, whereas the effects on 100-kDa OAS are dependent on
STAT1–2 heterodimers, a form of GAF. However, both ISGF3 and GAF
regulate STAT1 expression. Understanding the mechanism by which
IFN-activated STATs stimulate the expression of ISGs helps to
explain how IFN acts as the signal for maternal recognition of
pregnancy in ruminants.
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Acknowledgments |
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Footnotes |
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2 These authors contributed equally to this work.
Received September 12, 2000.
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A.P. Hess, A.E. Hamilton, S. Talbi, C. Dosiou, M. Nyegaard, N. Nayak, O. Genbecev-Krtolica, P. Mavrogianis, K. Ferrer, J. Kruessel, et al. Decidual Stromal Cell Response to Paracrine Signals from the Trophoblast: Amplification of Immune and Angiogenic Modulators Biol Reprod, January 1, 2007; 76(1): 102 - 117. [Abstract] [Full Text] [PDF]
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J. G. W. Fleming, T. E. Spencer, S. H. Safe, and F. W. Bazer Estrogen Regulates Transcription of the Ovine Oxytocin Receptor Gene through GC-Rich SP1 Promoter Elements Endocrinology, February 1, 2006; 147(2): 899 - 911. [Abstract] [Full Text] [PDF]
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 M. D. Stewart, J. Li, and J. Wong Relationship between Histone H3 Lysine 9 Methylation, Transcription Repression, and Heterochromatin Protein 1 Recruitment Mol. Cell. Biol., April 1, 2005; 25(7): 2525 - 2538. [Abstract] [Full Text] [PDF]
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S. Kim, Y. Choi, F. W. Bazer, and T. E. Spencer Identification of Genes in the Ovine Endometrium Regulated by Interferon {tau} Independent of Signal Transducer and Activator of Transcription 1 Endocrinology, December 1, 2003; 144(12): 5203 - 5214. [Abstract] [Full Text] [PDF]
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Y. Choi, G. A. Johnson, T. E. Spencer, and F. W. Bazer Pregnancy and Interferon Tau Regulate Major Histocompatibility Complex Class I and {beta}2-Microglobulin Expression in the Ovine Uterus Biol Reprod, May 1, 2003; 68(5): 1703 - 1710. [Abstract] [Full Text] [PDF]
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K. D. Carpenter, C. A. Gray, S. Noel, A. Gertler, F. W. Bazer, and T. E. Spencer Prolactin Regulation of Neonatal Ovine Uterine Gland Morphogenesis Endocrinology, January 1, 2003; 144(1): 110 - 120. [Abstract] [Full Text] [PDF]
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 A. Spagnoli, M. Torello, S. R. Nagalla, W. A. Horton, P. Pattee, V. Hwa, F. Chiarelli, C. T. Roberts Jr., and R. G. Rosenfeld Identification of STAT-1 as a Molecular Target of IGFBP-3 in the Process of Chondrogenesis J. Biol. Chem., May 17, 2002; 277(21): 18860 - 18867. [Abstract] [Full Text] [PDF]
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M. D. Stewart, Y. Choi, G. A. Johnson, L.-y. Yu-Lee, F. W. Bazer, and T. E. Spencer Roles of Stat1, Stat2, and Interferon Regulatory Factor-9 (IRF-9) in Interferon Tau Regulation of IRF-1 Biol Reprod, February 1, 2002; 66(2): 393 - 400. [Abstract] [Full Text] [PDF]
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Y. Choi, G. A. Johnson, R. C. Burghardt, L. R. Berghman, M. M. Joyce, K. M. Taylor, M. David Stewart, F. W. Bazer, and T. E. Spencer Interferon Regulatory Factor-Two Restricts Expression of Interferon-Stimulated Genes to the Endometrial Stroma and Glandular Epithelium of the Ovine Uterus Biol Reprod, October 1, 2001; 65(4): 1038 - 1049. [Abstract] [Full Text] [PDF]
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