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(Received for publication, June 27,
1995; and in revised form, August 3, 1995) From the
Transient transfection of expression vectors for various members
of the hematopoietin receptor family and STAT proteins into COS-1 cells
indicated that each receptor was capable of stimulating the DNA binding
activity of STAT1, STAT3, and STAT5B. However, gp130 preferentially
activated STAT1 and STAT3. Activation of STAT5B differed from that of
the other two in that the box 3 sequence motif in the cytoplasmic
domain of gp130 was not required. Moreover, STAT5B and STAT3 enhanced
gene transcription via separate regulatory elements. This study has
identified two potential signal transduction pathways by which
hematopoietin receptors, including the interleukin-6 receptor, control
transcription of acute phase plasma protein genes in hepatic cells.
The transcriptional regulation of acute phase plasma protein
genes in hepatic cells by IL-6 (
Figure 1:
Expression and analysis of STAT
proteins. Triplicate aliquots of whole cell extracts from H-35 cells
after 15 min treatment with IL-6 containing 5 µg (H-35-Std) of protein or from COS-1 cells transfected with
expression vectors for STAT5B (2.5 µg/ml) and PRLR and treated for
15 min with PRL containing 1 µg of protein (STAT5B) were
reacted with the oligonucleotides listed at the top (30,000 cpm;
300,000 cpm/ng). The complexes were separated by polyacrylamide gel
electrophoresis, and the autoradiogram was exposed for 16 h. Note
qualitative and quantitative differences in affinity. The positions of
SIF-A, -B, and -C and the STAT5B oligomeric complex (*) are indicated
on the left.
Differences in binding specificity for the probes emerged when
tested with STAT5B (Fig. 1). STAT5B did not detectably bind to
the SIE. The To define the activation of specific STAT proteins by gp130,
we transiently over expressed rat STAT1, STAT3, and STAT5B together
with the chimeric receptor G-CSFR-gp130 in COS-1 cells. The chimeric
construct permitted analysis of its signaling independent of the
endogenous gp130(11) . We verified that the STAT expression
vectors yielded abundant and approximately equal amounts of STAT
proteins (Fig. 2A; (6) ). To grade the
preference of gp130 for specific STAT proteins, we compared its action
with that of co-introduced IL-3R (Fig. 2B). IL-3R was
chosen because of its strong stimulation of transcription via HRRE in
hepatoma cells (12) and its difference from gp130 in lacking a
box 3 motif.
Figure 2:
Activation of STATs in COS-1 cells and
activation by gp130 and IL-3R. A, expression vectors for
G-CSFR-gp130(277) (1 µg/ml) and either for STAT5B or STAT3
(concentrations indicated) were transfected into COS-1 cells. Whole
cell extracts of duplicate subcultures (control and G-CSF-treated)
containing 5 µg of protein were analyzed by Western blotting for
STAT protein expression. Blots were processed simultaneously for
chemiluminescent reaction. B, COS cells were transfected with
expression vectors for G-CSFR-gp130(277), IL-3R
Both receptor types were capable of transducing the
signal to each STAT isoform. The comparison also indicated that IL-3R
preferred STAT5B, whereas gp130 preferred STAT1 and STAT3, consistent
with the action of native IL-6R in H-35 cells (Fig. 1). The EMSA
patterns as well as antibody supershift assays (not shown) did not
provide any evidence for appreciable formation of heterodimers between
STAT1 and STAT5B or between STAT3 and STAT5B. TB-2 contains two IL-6REs
in a 20-base pair span and was thus predicted to bind two STAT dimers.
Surprisingly, this probe did not produce detectable amounts of mixed
tetrameric complexes containing one homodimer each of STAT1 and STAT5B,
as judged from the absence of complexes with intermediate mobilities on
EMSA (Fig. 2B) or reacting to both anti-STAT1 and
anti-STAT5 (not shown). We hypothesized that either two different STAT
dimers were incompatible in simultaneous binding to TB-2, or that
STAT5B binds as a preformed tetramer. The results obtained with
pairwise combinations of STATs indicated a certain degree of
competition among STATs for activation by the receptors that was
correlated with the preferred usage of the particular STAT by the
receptor.
Figure 3:
Influence of box 3 motif on STAT
activation. COS-1 cells were transfected with expression vector for
G-CSFR-gp130(133) wild type (wt) or M3 (1 µg/ml each) and
STAT5B or STAT3 (2.5 µg/ml) and JAK2 (0.1 µg/ml). Whole cell
extracts were used for EMSA with TB-2 as probe. One reaction with
extract containing active STAT3 was incubated with anti-STAT3 to
supershift the STAT3-containing complex (wt + Ab).
From these results, we concluded that gp130 utilizes separate
mechanisms to activate STAT3 and STAT5B. The two pathways have distinct
requirements for cytoplasmic receptor domains, but both are dependent
on the action of JAKs. One consequence of JAK action is the tyrosine
phosphorylation of STATs, thereby inducing dimerization and
manifestation of DNA binding
activity(24, 25, 26) . Since direct binding
of STATs via their SH2 domain to a phosphotyrosine residue in the
receptor molecule is not mandatory for their activation(27) ,
an alternative mechanism for bringing STATs in contact with
receptor-bound kinases must exist. One possibility yet to be tested is
that STATs directly interact with the kinase or connector molecules. One prediction for the proposed mechanism of interaction between
receptors and STATs was that other hematopoietin receptors lacking a
box 3 sequence but utilizing JAK2 should also activate STAT5B with
comparable efficiency to IL-3R in our assay system. As anticipated,
PRLR and GHR, which have been associated with the STAT5
pathway(24, 26, 28) , promoted activation of
STAT5B (Fig. 4). Nevertheless, these receptors also showed
activation of STAT3, albeit at variable and much lower levels and only
when STAT3 was provided in sufficiently high concentrations (Fig. 4; (6) ).
Figure 4:
Action of GHR and PRLR. COS-1 cells were
transfected with expression vectors for GHR and PRLR (1 µg/ml each)
and for STAT3 or STAT5B (2.5 µg/ml) as indicated. STAT activities
were determined as in Fig. 2.
Functional screening of various regulatory elements
indicated that all elements containing a core sequence related to the
Figure 5:
Stimulation of transcription by STAT5B.
HepG2 cells were transfected with pHRRE-CAT (10 µg/ml) and
expression vectors for GHR and PRLR (1 µg/ml each) and increasing
amounts of STAT5B or STAT3 as noted. Subcultures were treated without
cytokines (control) or with PRL, GH, or IL-6. The change in
CAT activity was calculated relative to control cells without STAT
supplementation. Values represent means of two separate experimental
series.
In HepG2 cells, both GHR and PRLR were able to
control transcription, in part via STAT5B. This finding differs from
similar experiments with STAT5A in COS cells reported by Gouilleux et al.(29) , who observed that PRLR but not GHR or
erythropoietin receptor mediated enhanced gene transcription via the
To confirm
the role of STAT5B in hematopoietin receptor signaling leading to gene
transcription, we extended the analyses to other receptor combinations.
We focused on those hematopoietin receptors that had shown low action
in HepG2 cells and for which no autocrine pathway or response to serum
factors was detectable. Moreover, for some of these receptors, the
activation of STAT5 had been already reported (30, 31, 32) . We achieved
transcription-enhancing effects via HRRE and related GAS sequences with
c-Mpl, and box 3-deleted constructs of G-CSFR-LIFR(140),
G-CSFR-gp130(40), and G-CSFR(27). The most prominent effect of STAT5B
on transcription was, however, obtained with IL-2R and IL-4R (Fig. 6). STAT5B enhanced the signal of the transfected
receptor, resulting in a transcription of the reporter gene that
equaled or even exceeded the effect of the endogenous IL-6R. Moreover,
when this optimal experimental receptor system was used in combination
with the IL-6RE-CAT construct, the results illustrated the clear
difference in the regulatory actions of STAT5B and STAT3. STAT5B
enhanced transcription via HRRE but not via IL-6RE, and STAT3 was
ineffective via HRRE (Fig. 5) but enhanced transcription via
IL-6RE (Fig. 6). What still needs to be determined is the extent
to which STAT3 and STAT5, or functionally redundant factors, contribute
to the regulation of genes by IL-6 in hepatoma cells.
Figure 6:
Transcription control by IL-2R and IL-4R
via STAT5B. HepG2 cells were transfected with either pHRRE CAT or
pIL-6RE-CAT (10 µg/ml), expression vectors for IL-2R
This study
demonstrates that hematopoietin receptors use two distinguishable
pathways to regulate gene transcription. The following model is
proposed. The basic signaling pathway probably exerted by most if not
all hematopoietin receptors requires minimally the box 1 motif. Box 1
engages one of the JAK family members(33) , which recruits
primarily STAT5 and much less the other STATs. Upon phosphorylation,
the dimeric or oligomeric STAT5 interacts with GAS/PRE/TB-2-related
sequences. If the receptor bears a box 3 or related sequence, STAT 1,
STAT3(8) , or STAT6 (34) are also recruited to
receptors by using box 3 as docking site. The subsequent activation
process by the receptor-bound JAK may be similar to that affecting
STAT5. The genetic targets of STAT3 differ from that of STAT5; thus,
separate sets of genes may be controlled by specific members of the
STAT family. Although the precise action of STAT proteins as
transcription factors has yet to be defined, it is commonly assumed
that the binding of STATs to the DNA element enhances transcription of
the genes in cis. Although STAT1 and STAT6 are also
regulated by some of the hematopoietin receptors used in our study, no
transcription- controlling action of these STATs could be detected by
the approach of overexpression(6) . It is conceivable that
under physiological conditions STAT1 or STAT6 can interfere with or
modulate the action of the other STAT proteins by competition for
binding to the same DNA sequences. Unquestionably, the transfection
experiments are crude reconstitutions of the normal regulatory systems
operative in cells and may yield artificially exaggerated responses.
However, these experiments have emphasized the importance of (a) the relative concentrations of receptors, kinases, and
STATs and (b) the sequence specificity of the binding of STATs
to DNA response elements. A most notable effect also is that excess
amounts of JAKs lead to ligand-independent activation of STATs and
transcription, suggesting that under such conditions alternative
pathways that are generally unnoticed have become predominant.
Moreover, every transcription assay is performed in cells that
contribute a complex combination of endogenous factors, some of which
may significantly influence the observed regulatory events.
Volume 270,
Number 40,
Issue of October 06, pp. 23254-23257, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
)has been correlated with
the activation of DNA binding properties of STAT3 by the signaling
activity of
gp130(1, 2, 3, 4, 5) . The
suggested function of STAT3 as a transcription factor was supported by
the finding that overexpression of STAT3 and its activation by cytokine
receptor and Janus kinases resulted in enhanced transcription via
IL-6-responsive gene elements(6) . However, the model proposing
a principal role for STAT3 as a mediator of acute phase response (3, 7) needed to be refined because: 1)
gp130-dependent transcription via certain elements, such as the HRRE,
was found to be independent of STAT3(8) ; and 2) the acute
phase response of the liver included activation of not only STAT3 but
also of other members of the STAT protein family, such as
STAT5B(9) . (
)The study of the transcription control
mechanisms by specific STAT isoforms has been difficult primarily due
to the lack of adequate experimental assay systems. Recently, we have
developed techniques to reconstitute the function of hepatic and
non-hepatic hematopoietin receptors in transiently transfected hepatoma
cells(10) . We could define the cytoplasmic domains of the
signal transducing receptor subunits required for the induction of
transcription through specific regulatory
elements(8, 11) . This cell assay system was used to
characterize the specificity of STAT protein activation by
hematopoietin receptors. Two distinct signaling pathways were
identified: one specified by the box 3-dependent activation of STAT3
and transcriptional stimulation via an IL-6RE, and the other specified
by the box 3-independent activation of STAT5B and transcriptional
stimulation via HRRE.
Cells
HepG2 and COS-1 cells were cultured as
described (10) . Hormonal treatments were carried out in
serum-free medium containing 1 µM dexamethasone alone or
with 100 ng/ml recombinant human IL-2 (Cetus Corp.), IL-3 (Sandoz),
IL-4, G-CSF (Immunex Corp.), GH (Genentech), IL-6 (Genetics Institute),
or ovine PRL (National Hormone and Pituitary Program, lot ATP 10677C).Expression Vectors and CAT Reporter Gene
Constructs
Expression vectors for the following receptors have
been described previously(10, 11, 12) : human
IL-3R
(13) , IL-3R
(14) ,
IL-2R(15) , IL-2R(16) , IL-4R(17) ,
chimeric human G-CSFR-gp130(277), G-CSFR-gp130(133) (11) and
its box 3 mutant (M3, Y125A)(8) , rabbit GHR(18) , and
pigeon PRLR(19) . Expression vector for rat STAT1,
STAT3(6) , and STAT5B
consisted of the plasmid
SV-Sport1 (Life Technologies, Inc.) containing the cDNAs inserted into
the polylinker region. Plasmid EF-BOS-JAK2 (20) was provided by
Dr. D. M. Wojchowski (Pennsylvania State University, University Park,
PA). The CAT reporter gene constructs pHRRE-CAT and pIL-6RE-CAT have
been described(10) .Cell Transfection and Analysis
COS-1 cells were
transfected with plasmid DNA by the DEAE-dextran method (21) and HepG2 cells by the calcium phosphate
method(22) . The cell cultures were subdivided. Subcultures of
COS cells were maintained for 16 h in serum-free medium prior to the
activation of STAT proteins by treatment with cytokines for 15 min. DNA
binding activities of STAT proteins in whole cell extracts were
determined by EMSA(23) . Double standard oligonucleotides for
the high affinity SIEm67(23) , the mammary gland factor binding
site of the rat -casein gene (PRL response element, or PRE; (24) ), and TB-2, a duplicated IL-6RE sequence (TB-1) of the
rat -macroglobulin gene(2) , served as EMSA
substrates. The STAT1, STAT3 and STAT5B-containing complexes with PRE
and TB-2 were identified by supershift assay using 2 µg of
monoclonal anti-STAT1 (Transduction Laboratories), 0.5 µg of rabbit
anti-STAT3 (Santa Cruz Biotechnology), or 0.5 µl of antiserum
against STAT5 (generous gift of Dr. H. Wakao, DNAX). Aliquots (5
µg) of whole cell extracts were electrophoresed on a 6%
SDS-polyacrylamide gel, and the proteins were transferred to Immobilon
membrane (Millipore). The membranes were reacted with either rabbit
anti-STAT3 or anti-STAT5 (Transduction Laboratory) and then processed
for chemiluminescent reactions (Amersham). Transfected HepG2 cell
cultures were treated for 24 h with cytokines. CAT activities were
quantitated by testing serial dilutions of cell extracts, normalized to
the expression of the cotransfected marker plasmid
pIE-MUP(11) , and expressed relative to the value of the
untreated control cultures in each experimental series (defined as
= 1.0).
Activation of Multiple STAT Proteins by gp130
To
identify the STAT proteins activated by gp130, we employed three
oligonucleotides as diagnostic substrates: the high affinity
SIE(23) , the PRE of the -casein gene(24) , and
TB-2(2) . Each probe yielded a specific EMSA pattern of
IL-6-regulated DNA binding proteins in H-35 cells (Fig. 1). Both
STAT1 and STAT3 bound to the SIE, giving rise to the complexes SIF-A,
-B, and -C(23) . The -casein element was recognized
primarily by the STAT1 homodimers (co-migrating with SIF-C). The STAT
proteins contributing to the slow mobility TB-2 complex could not be
deduced from the relative position with co-migrating SIF complexes.
-casein element yielded two complexes: one
co-migrating with SIF-B and likely containing the predicted STAT5
dimer, and the other showing a much slower mobility and co-migrating
with the single complex observed with the dimeric TB-2. Since both
complexes reacted with anti-STAT5 detectable by supershift EMSA (data
not shown), the slow mobility complexes were interpreted to be
consistent with a STAT5B tetramer. The comparison of the patterns in Fig. 1also indicated that in extracts of IL-6-treated H-35
cells, STAT1 and STAT3 predominate, obscuring detection of
STAT5-containing complexes. We could, however, detect STAT5 in nuclear
extract of IL-6-treated cells by Western blot analysis (data not
shown).
and IL-3R (1
µg/ml each), and STAT1, STAT3, or STAT5B (2.5 µg/ml) as
indicated at the top. Triplicate subcultures were treated as
control or with IL-3 (3) or G-CSF (G) as shown at the bottom. Identical amounts of whole cell extracts were reacted
with SIE, -casein element, and TB-2, and processed for
EMSA.
Activation of STAT5B by gp130 Is Independent of the Box 3
Motif
Since gp130 activated STAT5B (Fig. 2B), we
asked whether this process, like the activation of STAT1 and
STAT3(8, 11) , was dependent on a functional box 3. We
transfected COS-1 cells with G-CSFR-gp130 in which the cytoplasmic
domain had been truncated to 133 residues. This minimal size gp130 with
three of the four box 3 motifs removed still activated STAT3 and
transcription via IL-6RE(8) . As expected, this construct also
mediated STAT5B activation that was comparable to the full-length gp130 (Fig. 3). The mutation Y125A in box 3 (M3; (8) )
abolished activation of STAT3 (no detectable complex with TB-2 (Fig. 3) or SIE (data not shown; (8) )), but did not
affect activation of STAT5B (Fig. 3). Based on data not shown, a
similar level of STAT5B activation was achieved with gp130 truncated to
65 residues. With the deletion of box 2 (40 residues left), STAT5B
regulation was substantially reduced. Hence, the cytoplasmic domain of
gp130 required for STAT5B regulation was the same as needed for
stimulating transcription via HRRE(8) . When an expression
vector for JAK2 was cotransfected, a ligand- and box 3-independent
activation of STAT5B was gained (Fig. 3) that was equivalent to
that observed previously for STAT1 and STAT3(6, 8) .
STAT5B and STAT3 Do Not Stimulate Transcription through
the Same Regulatory Elements
The data obtained with COS-1 cells
illustrated the preferences of hematopoietin receptors for STATs. The
question arose whether the differences in STAT patterns, in particular
the use of STAT5B, could be detected at the level of transcription. We
selected HepG2 cells as an assay system because transcriptional
regulation by various hematopoietin receptors could be reconstituted in
these cells(10, 12, 16) , and we expected to
find an enhanced responsiveness by overexpressed and receptor-activated
STAT proteins.-activating site (GAS) including the IL-4RE/GAS of the Fc
R1
gene,
-casein PRE, the IL-6RE of the
-macroglobulin gene, and, foremost, HRRE, were
responsive to STAT5B. Transfection of GHR and PRLR together with the
HRRE-CAT construct and increasing amounts of STAT5B expression vector
established a dose-dependent increase of CAT gene transcription (Fig. 5). The enhancing effect of STAT5B was noted on both the
basal and receptor-mediated transcription. The change in
transcriptional regulation via HRRE was STAT5B-specific because STAT3 (Fig. 5), STAT1, or STAT6 (data not shown; (6) ) proved
to be ineffective.
-casein element. Both studies concur in that the magnitude of
STAT5 activation by the receptor did not correlate well with the
magnitude of transcriptional induction. For instance, in Fig. 5,
neither GHR nor PRLR reconstituted an increase in transcription of
comparable magnitude with that by the endogenous IL-6R.
,
IL-2R and IL-4R (1 µg/ml each) and either increasing amounts
of STAT5B (noted in leftpanel) or STAT3 or STAT5B (5
µg/ml) (rightpanel). Subcultures were treated
with IL-2, IL-4, or IL-6, and the change in CAT activity was calculated
relative to control culture. Similar regulatory effects were measured
in three additional experiments.
)-activating site; G-CSF, granulocyte-colony
stimulatory factor; GH, growth hormone; HRRE, hematopoietin receptor
response element; PRE, prolactin response element; PRL, prolactin; -R,
receptor; RE, response element; SIE, sis-inducible element; STAT,
signal transducer and activator of transcription.
)
We thank Dr. D. M. Wojchowski for providing
pEF-BOS-JAK2; Drs. S. F. Ziegler and S. Kumaki for expression vectors
for IL-2R, IL-2R, and IL-4R; Drs. D. J. Tweardy and H. Wakao
for anti-STAT5; and Marcia Held and Lucy Scere for secretarial work.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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I. Behrmann, C. Janzen, C. Gerhartz, H. S.-V. de Leur, H. Hermanns, B. Heesel, L. Graeve, F. Horn, J. Tavernier, and P. C. Heinrich A Single STAT Recruitment Module in a Chimeric Cytokine Receptor Complex Is Sufficient for STAT Activation J. Biol. Chem., February 21, 1997; 272(8): 5269 - 5274. [Abstract] [Full Text] [PDF]
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D. W. White, K. K. Kuropatwinski, R. Devos, H. Baumann, and L. A. Tartaglia Leptin Receptor (OB-R) Signaling. CYTOPLASMIC DOMAIN MUTATIONAL ANALYSIS AND EVIDENCE FOR RECEPTOR HOMO-OLIGOMERIZATION J. Biol. Chem., February 14, 1997; 272(7): 4065 - 4071. [Abstract] [Full Text] [PDF]
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M. Ernst, A. Oates, and A. R. Dunn gp130-mediated Signal Transduction in Embryonic Stem Cells Involves Activation of Jak and Ras/Mitogen-activated Protein Kinase Pathways J. Biol. Chem., November 22, 1996; 271(47): 30136 - 30143. [Abstract] [Full Text] [PDF]
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S. P. Campos, Y. Wang, and H. Baumann Insulin Modulates STAT3 Protein Activation and Gene Transcription in Hepatic Cells J. Biol. Chem., October 4, 1996; 271(40): 24418 - 24424. [Abstract] [Full Text] [PDF]
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B. C. Xu, X. Wang, C. J. Darus, and J. J. Kopchick Growth Hormone Promotes the Association of Transcription Factor STAT5 with the Growth Hormone Receptor J. Biol. Chem., August 16, 1996; 271(33): 19768 - 19773. [Abstract] [Full Text] [PDF]
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U. Novak, A. Mui, A. Miyajima, and L. Paradiso Formation of STAT5-containing DNA Binding Complexes in Response to Colony-stimulating Factor-1 and Platelet-derived Growth Factor J. Biol. Chem., August 2, 1996; 271(31): 18350 - 18354. [Abstract] [Full Text] [PDF]
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C.-F. Lai, J. Ripperger, K. K. Morella, J. Jurlander, T. S. Hawley, W. E. Carson, T. Kordula, M. A. Caligiuri, R. G. Hawley, G. H. Fey, et al. Receptors for Interleukin (IL)-10 and IL-6-type Cytokines Use Similar Signaling Mechanisms for Inducing Transcription through IL-6 Response Elements J. Biol. Chem., June 14, 1996; 271(24): 13968 - 13975. [Abstract] [Full Text] [PDF]
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T. Kordula, J. Ripperger, K. K. Morella, J. Travis, and H. Baumann Two Separate Signal Transducer and Activator of Transcription Proteins Regulate Transcription of the Serine Proteinase Inhibitor-3 Gene in Hepatic Cells J. Biol. Chem., March 22, 1996; 271(12): 6752 - 6757. [Abstract] [Full Text] [PDF]
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P. A. Ram, S.-H. Park, H. K. Choi, and D. J. Waxman Growth Hormone Activation of Stat 1, Stat 3, and Stat 5 in Rat Liver J. Biol. Chem., March 8, 1996; 271(10): 5929 - 5940. [Abstract] [Full Text] [PDF]
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J. A. Ripperger, S. Fritz, K. Richter, G. M. Hocke, F. Lottspeich, and G. H. Fey Transcription Factors Stat3 and Stat5b Are Present in Rat Liver Nuclei Late in an Acute Phase Response and Bind Interleukin-6 Response Elements J. Biol. Chem., December 15, 1995; 270(50): 29998 - 30006. [Abstract] [Full Text] [PDF]
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