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Is Mediated through Phosphorylation of STAT-3 and STAT-1 Proteins1
The Population Council (S.J., P.L.M.) and The Rockefeller University (P.L.M.), New York, New York 10021
Address all correspondence and requests for reprints to: Dr. Patricia L. Morris, Center for Biomedical Research, The Population Council and The Rockefeller University, 1230 York Avenue, New York, New York 10021.
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Abstract |
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(IFN-), on signal
transducers and activators of transcription 3 and 1 (STAT-3 and STAT-1)
and on c-fos gene expression in primary Sertoli cells are
suggestive of their roles in differential function. Using the tyrosine
phosphorylation inhibitor, genistein, and electrophoretic mobility
shift assay, we show that IL-6 and IFN- induce nuclear factor STAT-3
and STAT-1 DNA-binding activity to the sis-inducible
element of c-fos in a genistein-dependent pathway.
Quantitative solution hybridization, Northern blot, and nuclear run-on
analysis show that differential induction of c-fos,
junB, and c-myc messenger RNA (mRNA) by these
cytokines occur at transcriptional levels. IL-6 stimulates
c-fos mRNA levels by 6-fold while increasing
junB levels by 2-fold. IFN- increases
c-fos message 2-fold, but has no effect on
junB mRNA levels. Furthermore, genistein treatment
blocks the induction of c-fos and junB gene
expression, demonstrating that tyrosine phosphorylation of STAT
proteins is involved in the cytokine regulation of the Sertoli
immediate early genes. H7, a serine/threonine phosphorylation
inhibitor, also blocks c-fos gene induction by IL-6 and
IFN-, but does not affect the DNA-binding activities of STAT-3 and
STAT-1. Finally, IL-6 treatment of Sertoli cells (3–6 h) increases the
amounts of activating protein-1 binding to activating protein-1 element
and c-myc transcription. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(IFN-) are multifunctional cytokines that
regulate cell function through tyrosine phosphorylation of latent
proteins (2). In many established cell lines, the binding of IL-6 and
IFN- to distinct membrane receptors activates several members of the
Janus kinase (Jak) family and signal transducers and activators of
transcription (STAT) transcription factors (3, 4, 5). IL-6 binds to the
IL-6 receptor (IL-6R
) with subsequent tyrosine phosphorylation of
the receptor and its associated binding component, gp130 mediated in
part by Jak1, Jak2, and Tyk2 activation and STAT3 phosphorylation.
IFN- binding to its -chain receptor unit and subsequent
phosphorylation of its ß-chain subunit by Jak1 and Jak2 kinases lead
to STAT1 phosphorylation and nuclear translocation (4). Phosphorylated
STAT-1 and STAT-3 homo- and/or heterodimerize and subsequently
translocate to the nucleus to interact with specific DNA response
elements and regulate the expression of targeted genes, including the
activating protein 1 (AP-1) family of transcription factors,
c-fos and junB (6, 7). Although the two STATs
have been shown to bind to the same regulatory element of several
different genes, they also can selectively interact with distinct and
specific elements in separate genes. Thus, these cytokines can direct
differential patterns of gene induction (8, 9, 10).
The expression of IL-6 and its receptor, ligand-mediated activation of
Sertoli Jak/STAT pathways, and subsequent gene expression are
consistent with testicular cytokine function as autocrine/paracrine
factors under noninflammatory conditions (7, 11, 12). In this
report we characterize the IL-6 and IFN- activation of STAT-3 and
STAT-1 proteins, and c-fos and junB gene
expression in primary cultures of rat Sertoli cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(Genzyme, Cambridge, MA) were dissolved in
0.1% BSA as 100-fold (5 µg/ml) and 500-fold (20 µg/ml; 100,000 U)
stock solutions, respectively. The final culture medium concentration
of each cytokine was 2.5 nM. Matched aliquots of 0.1% BSA
were used in control cultures. Genistein and H7 (Calbiochem) were
dissolved in dimethylsulfoxide (DMSO) and H2O,
respectively. Procedures involving the use of animals strictly followed the Guidelines for the Care and Use of Laboratory Animals set forth by the NIH.
Analysis of messenger RNA (mRNA) levels
Total RNA was extracted from Sertoli cells using the Trizol
reagent (Life Technologies, Grand Island, NY). Riboprobes were prepared
from plasmids containing complementary DNAs for rat c-fos
(SA = 6.6 x 108 dpm/µg) and human 18S
ribosomal RNA (rRNA; SA = 1.0 x 107 dpm/µg) as
described previously (14). Plasmids containing the complementary DNAs
for JunB, c-jun, and c-myc were
obtained from American Type Culture Collection (Rockville, MD). For
solution hybridization assays, duplicates of total RNA extracts (20–30
µg) were hybridized in 30 µl buffer (10 mM EDTA, 0.3
M NaCl, 0.5% SDS, and 10 mM
N-Tris-[hydroxymethyl]methyl-2-amino-ethanesulfonic acid,
pH 7.4) containing 32P riboprobe, 150,000 dpm for the
c-fos or junB riboprobes or 80,000 dpm for the
18S riboprobe, for 4 h at 75 C. After hybridization, 300 µl 0.3
M NaCl, 5 mM EDTA, and 10 mM
Tris-HCl, pH 7.4, containing 40 µg/ml ribonuclease (ribonuclease) A
and 2 µg/ml ribonuclease T1 were added to each tube, and the samples
were incubated at 30 C for 1 h. The samples were precipitated with
1 ml 5% trichloroacetic acid, 0.75% sodium pyrophosphate, and one
drop of 0.5% BSA and were collected onto glass fiber filter paper
(Brandel, Gaithersburg, MD) using a 24-place cell harvester. The
filters were counted by liquid scintillation in 5 ml Hydrofluor
scintillation solution (National Diagnostics, Manville, NJ). Comparison
was made with standard calibration curves to quantify the
c-fos and junB mRNA transcripts and the 18S rRNA
levels. c-fos and junB mRNA levels were then
normalized to the level of control samples (1 pg/µg 18S rRNA).
Northern blot analysis was performed using 20 µg total RNA by the
glyoxal method (15).
For nuclear run-on studies, 3–5 x 107 cells were untreated or treated with IL-6 for the indicated times, and the nuclei were isolated in 10 mM Tris-HCl (pH 7.4), 10 mM NaCl, 3 mM MgCl2, and 0.5% Nonidet P-40. The nuclei were then resuspended in 50 mM Tris-HCl (pH 8.3), 40% glycerol, 5 mM MgCl2, and 0.1 mM EDTA, and the RNA was labeled in 10 mM Tris-HCl (pH 8.0); 0.3 M KCl; 5 mM dithiothreitol; 1 mM each of ATP, CTP, and GTP; and 100 µCi UTP (3000 Ci/mmol; Amersham Life Science, Arlington Heights, IL) for 30 min at 30 C as previously described (16). The nuclei were digested with deoxyribonuclease and proteinase K, and the newly synthesized RNA was purified using Trizol reagent (Life Technologies, Grand Island, NY). For slot blot analysis, 10 µg linearized c-fos and c-myc, 5 µg junB and c-jun, or 10 ng 18S rRNA (plus 10 µg transfer RNA carrier) plasmids were applied to nylon membranes (MSI, Westboro, MA) and then hybridized with the run-on transcripts for 36 h at 65 C and washed at 65 C in 2 x SSC (0.3 M NaCl and 30 mM sodium citrate, pH 7.0).
Nuclear extract preparation and electrophoretic mobility shift
assay (EMSA)
Nuclear extracts were prepared from unstimulated or
stimulated primary Sertoli cells as previously described (2, 17). The
oligonucleotide sequences used are as follows: rat c-fos
sis-inducible element (SIE) oligonucleotide,
5'-TCGACTGTTCCCGTCAATC-3' (18); m67 oligo,
5'-CATTTCCCGTAAATCGTCGA-3' (19); and Fc oligo,
5'-TCGACGCATGTTTCAAGGATTTGAGATGTATTTCCCAGAAAAGGCTCGA-3' (20). The
complementary oligos were annealed in 100 mM Tris-HCl (pH
8.0) and 50 mM MgCl2 over a period of 3 h.
The AP-1 oligo was obtained from Promega Corp. (Madison, WI), and all
other oligonucleotides were synthesized by Midland Corp. (Midland, TX).
The oligo probes were end labeled with T4 polynucleotide kinase and
-ATP. Nuclear extracts (2–10 µg) were incubated in a final volume
of 12 µl in 20 mM HEPES (7.9), 40 mM KCl, 1
mM MgCl2, 0.1 mM EGTA, 0.5
mM dithiothreitol, and 4% Ficoll for 20 min at room
temperature with the probe (150,000–200,000 cpm, 1 ng; 40,000 cpm for
AP-1 oligo). Antiserum to STAT-3 protein (kindly provided by J. E.
Darnell, Jr., Rockefeller University, New York, NY) was preincubated
with nuclear extracts for 10 min before the addition of the probe. For
the AP-1 supershift assay, the c-fos antibody (Santa Cruz
Biotechnology, Santa Cruz, CA) was preincubated with the extracts
overnight at 4 C before addition of the probe. The reaction products
were fractionated on a 4% nondenaturing polyacrylamide gel (29:1,
acrylamide-bis) in 0.25% Tris borate/EDTA that were prerun for 30 min
at room temperature.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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activate STAT-3 and STAT-1 transcription factors
in primary Sertoli cells receptor that binds STAT-1 and STAT-4, to study the context
requirements and screen for STAT-DNA binding in Sertoli cells during
IL-6 and IFN- stimulation. EMSA indicates that IL-6 preferentially
induces nuclear binding of STAT-3 (and some STAT-1) protein (Fig. 1
, lanes 2, 5, and 8), whereas IFN- activates STAT-1
protein (lanes 3, 6, and 9). Our data show that the m67 oligo interacts
with STAT-1 protein (lane 3) with similar binding to STAT-3 protein
(lane 2), whereas in the same extracts the c-fos SIE oligo
bound STAT-1 protein (lane 6) better than STAT-3 protein (lane 5).
Finally, the Fc receptor oligo only interacts with STAT-1 protein
(lane 9), indicating the absence of a STAT-3 binding consensus element
(lane 8).
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shows that rapid activation by IL-6 of
DNA-binding activity of STAT-3 protein to the m67 oligo occurs after 15
min to 6 h of treatment of Sertoli cells (lanes 1–6); the maximal
induction is observed at 15 min. Addition of a STAT-3 antiserum
supershifts this complex (lane 7) demonstrating that this nuclear
factor is STAT-3. The addition of 5-, 10-, or 50-fold unlabeled m67
oligo (lanes 8–10) abolishes the gel shift complex further, indicating
specificity. An IL-6 time course showing increasing AP-1 binding to the
nuclear extracts reveals AP-1 activation (Fig. 2B) after 3 or 6 h
of IL-6 treatment (Fig. 2B, lanes 5 and 6). Addition of
c-fos antibody (lane 7) or unlabeled AP-1 oligo (lanes
8–10) significantly reduces this binding. Although the addition of
STAT-3 antiserum supershifts a concise band (Fig. 2A, lane 7), addition
of c-fos antibody reduces the AP-1 binding, suggesting that
the AP-1 complex is made of multiple family proteins.
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requires tyrosine, but not serine/threonine, phosphorylation of
latent proteins, compare lane 2 to lane 3). Similarly, a 3-h
genistein preincubation before IFN- treatment inhibits STAT-1
binding to the SIE oligo (Fig. 3B, compare lane 2 to lane 3). Addition
of DMSO vehicle has no effect on STAT-1 or STAT-3 induction (Fig. 3, A
and B, lane 4). Pretreatment of Sertoli cells with the serine/threonine
inhibitor, H7 (100 µM), does not affect the binding of
STAT-3 or STAT-1 to the SIE probe (data not shown).
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, A and B). In a time-course study, we previously
showed that IL-6 and IFN- increase the steady state levels of
cytoplasmic c-fos mRNA by 6- and 2-fold after 45
min of treatment, respectively (7). Figure 5 shows the
results of quantitative solution hybridization and a representative
Northern blot analyses of a time course for junB mRNA
induction. In contrast, whereas IL-6 significantly increases
junB mRNA levels by 2-fold after 30–45 min of treatment
(Fig. 5A), IFN- did not affect junB mRNA levels, except
for a moderate increase after 2 h of treatment (Fig. 5B).
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in the presence or absence of genistein and/or H7 (6, 20). Quantitative
solution hybridization assays were used to measure c-fos and
junB mRNA levels in total RNA extracts after different
cytokine treatments of Sertoli cells. IL-6 increased steady state
c-fos mRNA levels by 6-fold, whereas IFN- induced
c-fos transcription by 2-fold after 45 min of treatment. A
3-h pretreatment of Sertoli cells with genistein (100 µg/ml) or a 1-h
pretreatment with H7 (100 µM) inhibited induction by both
IL-6 and IFN-, abolishing any increase in c-fos mRNA
levels (Fig. 6A). Similarly, pretreatment with genistein
inhibited IL-6 induction of junB message (Fig. 6B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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activate homo- or
heterodimeric STAT proteins, STAT-3 and STAT-1, respectively, to induce
differential expression of overlapping sets of genes by binding to DNA
response elements (8). In HepG2 cells, IL-6 activates the distinct
nuclear factor STAT-3, which requires tyrosine kinase activity to bind
to the junB IL-6 response element and induce junB
expression. In contrast, IFN- failed to cause STAT-1 DNA binding to
this element or the transcriptional activation of junB (6).
Our present findings also indicate a differential regulation of Sertoli
junB and c-fos gene expression by IL-6 and
IFN-.
These two cytokines may also differentially regulate gene expression
based on the sequence of the palindrome consensus element that is
present in a specific gene (21). Although the sequence of the
palindrome varies in different genes, its context is frequently based
on the initially reported IFN- activation site TTCCNNNAA (3, 5). The
spacing between the half-sites of the palindrome also seem to determine
selective STAT binding (22). IL-6 activation (STAT-3) has been shown to
require a DNA palindrome sequence of 4 bp spacing, while 5 bp spacing
is needed for IFN--activated binding (STAT-1) (22). In our study the
three oligos interacted efficiently with IFN--activated STAT-1
protein, indicating an analogous responsive element within them (a core
sequence of TTCCCNNA/CA present in all three oligos). However, in
IL-6-activated Sertoli cells, STAT-3 only bound m67 and
c-fos SIE elements showing enhanced binding for m67,
suggesting that the nucleotides N6 and N7 are required for STAT-3
binding. The enhanced binding of m67 oligo compared to that of human
c-fos SIE oligo (which has the same nine core nucleotides as
the rat SIE) appears to result from the removal of nonspecific protein
binding to the m67 probe (19) and results from a change of C8 to A8.
Thus, changes in the nucleotides N6, N7, and A8/C8 substantially alter
STAT-3 binding in Sertoli nuclear extracts.
A third modification in a cytokine response element includes the
association with other regulatory sequences, for instance the
junB cAMP response element (CRE) or the c-fos
serum response element (SRE). The IL-6 response element of
junB contains a CRE element that is required for IL-6
responsiveness. Furthermore, this composite element binds a CRE-binding
protein as well as STAT-3 (23, 24). In the c-fos promoter,
the SRE and SIE elements are both implicated in the growth factor
regulation of c-fos, whereas transfection studies have shown
that platelet-derived growth factor and colony-stimulating factor 1
regulate the c-fos promoter through a synergism between the
SRE and the SIE elements (25). Using EMSA, we show that IL-6 and
IFN- induce rapid and specific interaction of both STAT-3 and STAT-1
proteins with the c-fos SIE oligo, whereas longer treatment
of 3–6 h with IL-6 increases nuclear AP-1 proteins that bind to the
AP-1 oligonucleotide, consistent with an increase in nuclear Fos
protein (and/or JunB protein). The SRE oligonucleotide, however, does
not interact with IL-6-stimulated Sertoli nuclear proteins during 15
min to 6 h of IL-6 treatment (data not shown). In transfection
studies of various other cells the SRE, SIE, and AP-1 elements are
required for stimulation by growth factors. Similar analyses are needed
to evaluate the complex roles of these elements in c-fos
gene regulation by IL-6 and IFN- in Sertoli cells.
Induction of transcription of the immediate early gene family is
a crucial first step in response to various extracellular stimuli (26).
Cytokine activation of genes, including junB, appears to be
mediated through STAT protein-DNA response element interactions that
require phosphorylation by distinct protein kinases (6). Stimulation of
junB gene in HepG2 cells is dependent on both a tyrosine
kinase and an H7-sensitive serine-threonine protein kinase pathway,
whereas only tyrosine phosphorylation is required to activate STAT
binding in EMSA (6). Tyrosine phosphorylation occurs at a specific
tyrosine residue in the C-terminal of the STAT protein sequentially
activating homo- or heterodimerization of the STAT proteins and
subsequent response element interactions (17, 27). We previously showed
that IL-6 and IFN- increase Sertoli cell c-fos mRNA
levels dependent on actinomycin D, but not on cyclohexamide treatment
(7). In the present study IL-6, but not IFN-, increases
junB mRNA levels, and furthermore, the IL-6 induction of
c-fos, junB, and c-myc gene expression
occurs at transcriptional levels. Finally, the tyrosine phosphorylation
inhibitor, genistein, blocked both STAT binding and c-fos
and junB gene induction, providing direct evidence that
tyrosine phosphorylation of STAT proteins is involved in the cytokine
regulation of Sertoli cell immediate early genes, and this
transcriptional activation is presumably mediated by binding of the
STAT proteins to the c-fos and junB SIE elements.
In contrast, the serine/threonine phosphorylation inhibitor, H7,
inhibited transcriptional activation by the cytokines, but had no
effect on STAT-oligonucleotide binding, as previously shown with HepG2
cells (see above). These data thus suggest that tyrosine
phosphorylation events are needed for nuclear translocation and
STAT-DNA binding, whereas additional serine/threonine phosphorylation
of STAT proteins is required for transcriptional activations. Indeed,
immunoprecipitation studies have shown two forms of STAT-3 and STAT-1
proteins that differ because of a time-dependent secondary
serine/threonine phosphorylation event (28, 29, 30, 31). However,
transcriptional activation of these immediate early genes by serine
phosphorylation of other important signaling pathways, such as
mitogen-activating protein kinase, nuclear factor IL-6, and protein
kinase C, cannot be ascertained at present (32, 33).
The AP-1 family of transcription factors is composed of fos and jun gene products that regulate gene expression by binding to the AP-1 element of late response as well as their own genes. Whereas c-fos-junB complexes appear to activate transcription, c-fos-c-jun heterodimers are negative regulators of AP-1 function (34, 35). c-myc gene expression is also rapidly induced in response to growth factors and cytokines (such as platelet-derived growth factor, lipopolysaccharides, and colony-stimulating factor) independent of new protein synthesis and the commonly following c-fos induction (36, 37, 38, 39). Two SIF-binding sites have been found in c-myc promoter, but it is not yet known whether they regulate c-myc gene expression by binding to specific STAT proteins (39, 40). Expressed c-myc transcription factor also forms heterodimers (with another factor, max) to differentially repress or induce gene expression by binding to specific DNA response elements (41, 42).
In summary (Fig. 7), we show for the first time that
testicular cytokines can activate and translocate STAT-3 and STAT-1
proteins to the nucleus, and whereas both increase c-fos
message, only IL-6 induces junB gene expression. IL-6
stimulation of Sertoli cells also increases c-myc
transcription and AP-1 DNA binding, albeit with a longer onset of
nuclear factor activation. FSH has been shown to stimulate both IL-6
expression and production (11, 43). Previous studies suggest a role for
IL-6 in regulating meiotic DNA synthesis (44). Although the mechanisms
are largely unknown, cytokines and growth factors play important roles
in reproduction, mediating both the proliferation and differentiation
of cells in the testis. We previously demonstrated the expression of
mRNAs for various components of the IL-6 signaling pathway (Fig. 7)
(11, 12) (our unpublished observations). The current study provides
functional insight to these studies. Primary Sertoli cells thus provide
a valuable nonhematopoietic system for analyzing differential
mechanisms involved in the transduction of IL-6 and IFN- signals
from the receptor to the regulatory elements of several responsive
genes in the seminiferous tubules.
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Acknowledgments |
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Footnotes |
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Received January 30, 1997.
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References |
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in Sertoli cells. Endocrinology 137:4638–4743
via the
interleukin 6-responsive element. Biochem J 309:63–67
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