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Volume 272, Number 49, Issue of December 5, 1997
pp. 30607-30610
(Received for publication, October 9, 1997)
From the ABSTRACT Interleukin-6 (IL-6) and glucocorticoids are
important mediators of inflammatory and immunological responses.
Glucocorticoids are known to synergistically enhance IL-6-mediated
cellular responses. We now show that IL-6 also has a synergistic effect
upon glucocorticoid signaling. In particular, IL-6-activated STAT3
associates with ligand-bound glucocorticoid receptor to form a
transactivating/signaling complex, which can function through either an
IL-6-responsive element or a glucocorticoid-responsive element. These
findings reveal a new level of interaction between these two crucial
signaling cascades and indicate that activated STAT3 can also act as a
transcriptional co-activator without direct association with its DNA
binding motif.
INTRODUCTION The control of gene expression by biological mediators is tightly
regulated through activation of distinct transcription factors. With
respect to IL-6,1 key
transcriptional events are controlled through activation of
transcription factor STAT3 (1-3). Activated STAT3 forms a homodimer
that translocates to the nucleus, where it enhances transcription
through association with a highly conserved palindromic DNA binding
motif (TTC(N)nCAA) (1-5). Recent publications have shown that
STAT3 also participates in the signaling events elicited by other
cytokines and growth factors, including IL-10, IL-11, epidermal growth
factor, growth hormone, platelet-derived growth factor, and leptin (1,
6-10).
Glucocorticoids are important mediators of the immune system and
modulate the biological activities of inflammatory cytokines, such as
IL-6 (11-14). Following binding to the latent intracellular glucocorticoid receptors (GR), the ligand-receptor complex translocates to the nucleus, where it activates transcription of downstream genes
through interaction with the glucocorticoid-responsive element (GRE)
(15-17). Recent studies have shown that the GR also regulates other
signaling events through interaction with either transcription factors,
such as AP-1 (Jun and Fos) (18-20), NF- It has long been recognized that glucocorticoids synergize the IL-6
response (11, 12, 28, 29). Examination of the synergistic relationship
between glucocorticoid and IL-6 signaling identified a novel function
for STAT3. We show that IL-6-activated STAT3 interacts with
ligand-bound GR to augment glucocorticoid signaling without association
with a STAT DNA binding motif. In this context, STAT3 is a potent
co-activator of the glucocorticoid receptor.
EXPERIMENTAL PROCEDURES Rat hepatoma H4IIE cells or
COS-7 cells were cultured in minimal essential medium containing 10%
fetal bovine serum (charcoal-absorbed to remove glucocorticoids) (30).
Transfection experiments were performed using the Lipofectin reagent
(Life Technologies, Inc.) or calcium phosphate precipitation (31). All
transfections were performed in 100-mm culture dishes using 40%
confluent cells. After 16 h of transfection, the cells were
trypsinized and split into 12-well plates for further treatment.
12 h later, cells were stimulated for an additional 16 h.
Recombinant mouse IL-6 was used at 100 ng/ml, and dexamethasone was
used at 10 Cell lysates were
prepared (33), and luciferase and H4IIE cells were stimulated
with IL-6 (100 ng/ml) or dexamethasone (10 EMSA were performed as described
previously (33, 36). The DNA probe ( RESULTS AND DISCUSSION The rat hepatoma cell line H4IIE possesses functional IL-6 and
glucocorticoid signaling pathways (33, 38). We transiently transfected
these cells with two distinct luciferase reporter constructs to
elucidate the mechanism of synergy between IL-6 and glucocorticoids.
The first construct (Fib-Luc) contains the proximal promoter region of
the rat
[View Larger Version of this Image (19K GIF file)]
It has been proposed that synergy between IL-6 and glucocorticoids in
hepatoma cells occurs through glucocorticoid-enhanced expression of
IL-6 signaling components, namely the IL-6 receptor and gp130 (28, 29).
However, this does not explain the synergy observed using the MMTV-Luc
construct (Fig. 1B). To determine the importance of the IL-6
signaling components in IL-6/glucocorticoid synergism, we utilized
COS-7 cells to perform reconstitution experiments. COS-7 cells do not
respond to either IL-6 or glucocorticoids because expression of the
IL-6 receptor, gp130, STAT3, and the GR is extremely low in these cells
(3, 23, 39). The glucocorticoid (23) and IL-6 signaling pathways can be
restored in COS-7 cells through the introduction of expression vectors
encoding for the appropriate signaling components, the IL-6 receptor,
gp130, STAT3, and the GR (Fig. 2).
Co-transfection with the Fib-Luc reporter construct in this context
confirms restoration of the IL-6 response (Fig. 2A). The
simultaneous introduction of the GR with IL-6 signaling components
resulted in an enhanced responsiveness to IL-6 and dexamethasone.
Experiments using the MMTV-Luc construct (Fig. 2B) showed
that dexamethasone signaling could be re-established in COS-7 cells
through expression of the GR. Transfection with the IL-6 receptor,
gp130, and STAT3 had no effect on MMTV-Luc luciferase activity;
however, upon co-transfection with the GR, a synergistic response was
observed after stimulation with IL-6 and dexamethasone. It should be
pointed out that transfected cells possessing all the components but
devoid of STAT3 showed no synergism. This result clearly defines the
central role of STAT3 in synergistically enhancing glucocorticoid
signaling. The binding of STAT3 to a conserved TTCTGGGAA motif is the
classic mechanism for STAT3 action (2, 6, 37). However, our
observations suggest that STAT3 can modulate GR signaling independent
of IL-6RE binding.
[View Larger Version of this Image (29K GIF file)]
Ligand-bound GR can directly activate target gene transcription through
the GRE (17). Furthermore, this receptor-ligand complex can modulate
gene expression independently of DNA binding by associating with other
transcription factors or nuclear co-factors (17, 19, 20, 23-26). We
postulated that STAT3 might interact directly with the GR, thereby
enhancing the transactivation of each component through its responsive
element. Co-immunoprecipitation experiments were performed using
nuclear extracts obtained from H4IIE cells (Fig.
3). Proteins were immunoprecipitated with
an anti-GR antibody and visualized by Western blotting using a STAT3 specific antibody (Fig. 3A). A STAT3-GR complex was detected
only in extracts obtained from cells co-stimulated with IL-6 and
dexamethasone. The STAT3-GR complex was also detected when the
anti-STAT3 antibody was used for immunoprecipitation and the anti-GR
antibody for Western blot analysis (Fig. 3B). A possible
functional role for this complex was demonstrated by EMSA using an
oligonucleotide containing a high affinity STAT3 binding site (37).
IL-6 stimulation of H4IIE cells induced activation of STAT3 (Fig.
3C, lanes 1-4). The inclusion of either an
anti-GR antibody (lane 6) or anti-STAT3 (lane 7)
in the EMSA reaction affected the protein-DNA complex. In particular,
anti-GR antibodies blocked complex formation (lane 6),
whereas antibodies to STAT3 supershifted the complex (lane 7). The inclusion of an equivalent amount of control antibody had
no effect (lanes 5). These data indicate the presence of
both the GR and STAT3 in a protein-DNA complex. Activated STAT3 is, therefore, able to bind the IL-6RE while associated with ligand-bound GR. Experimental attempts to show the STAT3-GR complex bound to a GRE
probe were unsuccessful because of the weak binding of the glucocorticoid-induced complex to the GRE probe (data not shown).
[View Larger Version of this Image (31K GIF file)]
It is known that GR interacts with certain transcription factors (17).
The interaction between the GR and AP-1 prevents their binding to
either the AP-1 site or the GRE site and antagonizes the
transactivational capacities of both regulators (19, 20). The
interaction between the GR and STAT5 enhances STAT5-mediated transactivation but diminishes GR function at the GRE site (23). Our
results suggest a third type of interaction, which leads to the
synergistic transactivation at both the IL-6RE and the GRE. We have
demonstrated the formation of a STAT3-GR complex which can bind to the
IL-6RE. In this case, GR can act as a co-activator. However, we can not
fully reconstitute the synergism using the Fib-Luc construct in COS-7
cells (Fig. 2A), suggesting that the STAT3/GR complex is
insufficient for the strong synergy observed through the IL-6RE (Fig.
1A); additional factors may be required. On the other hand,
we have shown that STAT3 is central to the synergy activated through
the GRE (Figs. 1B and 2B). In this case, STAT3 is
a potent co-activator of GRE-mediated transcription, independent of
IL-6RE binding. These findings reveal a novel level of interaction
between the IL-6 and glucocorticoid signaling pathways and suggest that
STAT3 may modulate other glucocorticoid actions. Furthermore, since
STAT3 and the GR have important roles in multiple cellular processes,
such as cell growth and differentiation, cell cycle control, apoptosis,
and development (32, 40-46), and since STAT3 is activated by numerous
mediators other than IL-6, such as platelet-derived growth factor,
epidermal growth factor, growth hormone, and leptin (10, 47), the
observed interaction between STAT3 and the GR may have broad biological
implications.
FOOTNOTES ACKNOWLEDGEMENTS We thank Drs. James E. Darnell, Jr., Zhong
Zhong, Zilong Wen, Michael Karin, David Barry, and Bahiru Gametchu for
providing the valuable materials used in this work.
REFERENCES
COMMUNICATION:
STAT3 Acts as a Co-activator of Glucocorticoid Receptor
Signaling*
,, and¶
Department of Cell Biology and the
§ Department of Pediatrics, Pulmonary Division, University
of Alabama at Birmingham, Birmingham, Alabama 35294
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
B (p65) (21, 22), and STAT5
(23), or nuclear co-factors, such as NCoR (24), CBP/p300, and pCAF (25,
26). These findings demonstrate that transcription factors also
participate in signaling through direct protein/protein interaction
with other transcriptional regulators (27).
6 M. For co-transfection assays, 5 µg of the reporter constructs were mixed with 5 µg of p
Act-GRwt
(32), 2.5 µg of pCMV/IL-6R, 2.5 µg of pCMV/gp130, and 2.5 µg of
pCMV/STAT3. An empty plasmid (pRc/CMV) was used to normalize the total
amount of DNA in each transfection. For each transfection, 1 µg of
pRSV-Gal vector (Promega) was always included to standardize
transfection efficiency.
-Galactosidase Assays
-galactosidase activities were
measured using appropriate detection kits (Promega).
6
M) for 1 h. Nuclear extracts were prepared as
described previously (33). Nuclear extracts were precleared with
protein A and protein G-agarose in HEGN050 buffer (10 mM
HEPES (pH 8.0), 1 mM EDTA (pH 8.0), 10% glycerol, 50 mM NaCl) containing 0.1% Triton X-100 (34) and then
immunoprecipitated with either 1 µg of monoclonal anti-glucocorticoid receptor antibody (BuGR2) or 1 µg of monoclonal anti-STAT3 antibody (S21320, Transduction Laboratories). Antigen-antibody complexes were
isolated using protein A and protein G-agarose and washed four times in
HEGN050 buffer containing 0.1% Triton X-100 (34). Protein samples were
denatured, separated by SDS-polyacrylamide gel electrophoresis, and
electroblotted onto polyvinylidene fluoride (PVDF) membrane for Western
blot analyses with either S21320 or BuGR2 (35).
2-macroglobulin)
used for EMSA (5
-GATCCTTCTGGGAATTCCTA-3) is derived from the IL-6RE
of the 2-macroglobulin gene promoter (36, 37). For
supershift assays, nuclear extracts were preincubated for 1 h at
4 °C with 4 µg of control antibody (anti-fibrinogen), BuGR2
(monoclonal anti-GR antibody), or polyclonal anti-STAT3 antibody (C20,
Santa Cruz) followed by standard EMSA procedures.
-fibrinogen gene (
300 to +54 base pairs), which has three
IL-6-responsive elements (IL-6RE) but no glucocorticoid-responsive
element (GRE) (33). As expected, IL-6, but not dexamethasone, enhanced
luciferase activity in these transfected cells. However, when IL-6 and
dexamethasone were added together, the response was synergistic (Fig.
1A). The IL-6/dexamethasone synergy observed on the Fib-Luc construct is dependent on the integrity
of all three IL-6REs, since mutation of any of these sites affects the
synergistic response (33). The MMTV-Luc construct contains the mouse
mammary tumor virus long terminal repeat, which has four GRE sites
(23), but no IL-6RE. Although luciferase activity was not enhanced by
IL-6, a synergistic response was again measured when cells were
co-stimulated with IL-6 and dexamethasone (Fig. 1B). These
data demonstrate that the IL-6/glucocorticoid synergism can occur via
either an IL-6RE- or GRE-containing promoter.
Fig. 1.
Mutual functional synergism between IL-6 and
glucocorticoid. Transient transfections were performed in rat
hepatoma H4IIE cells, using the Fib-Luc (33) (A) and
MMTV-Luc (B) reporter constructs. IL-6 or dexamethasone
treatments are as indicated. The results are presented as fold
induction of luciferase activity (arbitrary light units) over control
levels from triplicate experiments, and the error bars
represent the standard deviations. The diagrammatic structure of the
reporter construct is presented below each panel.
Fig. 2.
Reconstitution of the IL-6/glucocorticoid
synergism in COS-7 cells. Transient co-transfection experiments
were performed in COS-7 cells. Expression vectors encoding for the IL-6
receptor (IL-6R), gp130, STAT3, and the glucocorticoid
receptor (GR) were co-transfected with either the Fib-Luc
(A) or MMTV-Luc (B) reporter constructs. IL-6 or
dexamethasone treatments are as indicated. The results are presented as
fold induction of luciferase activity (arbitrary light units) over
control levels from triplicate experiments, and the error
bars represent the standard deviations.
Fig. 3.
STAT3 and GR form a complex. Nuclear
extracts were prepared from H4IIE cells (33) and subjected to
immunoprecipitation with 1 µg of the monoclonal anti-glucocorticoid
receptor antibody BuGR2 (35) (A), the monoclonal anti-STAT3
antibody S21320 (Transduction Laboratories) (B), or control
antibody (anti-human fibrinogen antibody) (lanes 5 and
10). Immunoprecipitated complexes were separated by
SDS-PAGE, electroblotted onto PVDF, and probed with either anti-STAT3
or BuGR2, as indicated. The protein bands were visualized by ECL.
C, EMSA was performed using a 32P-labeled
2-macroglobulin oligonucleotide probe (33, 36, 37).
Lanes 1-4 show the IL-6 induction of STAT3 DNA binding. Supershift analyses were performed by including either a control antibody (anti-human fibrinogen) (lanes 5), BuGR2 (anti-GR
antibodies) (lanes 6), or -STAT3 (polyclonal anti-STAT3
antibody, C22, Santa Cruz) (lanes 7) in the EMSA reactions.
The arrow on the right and S indicate
the supershifted band.
¶
To whom correspondence should be addressed: Dept. of Cell
Biology, BHSB Suite 680, University of Alabama at Birmingham,
Birmingham, AL 35294-0005. Tel.: 205-934-7596; Fax: 205-934-0950.
1
The abbreviations used are: IL, interleukin;
STAT, signal transducer and activator of transcription; GR,
glucocorticoid receptor; GRE, glucocorticoid-responsive element; JAK,
Janus kinase; MMTV, mouse mammary tumor virus; PVDF, polyvinylidene
fluoride; BuGR2, a monoclonal anti-glucocorticoid receptor antibody;
EMSA, electrophoretic mobility shift assay.
Volume 272, Number 49,
Issue of December 5, 1997
pp. 30607-30610
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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W. Doppler, M. Windegger, C. Soratroi, J. Tomasi, J. Lechner, S. Rusconi, A. C. B. Cato, T. Almlöf, J. Liden, S. Okret, et al. Expression Level-Dependent Contribution of Glucocorticoid Receptor Domains for Functional Interaction with STAT5 Mol. Cell. Biol., May 1, 2001; 21(9): 3266 - 3279. [Abstract] [Full Text]
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C. T. Sherman and A. R. Brasier Role of Signal Transducers and Activators of Transcription 1 and -3 in Inducible Regulation of the Human Angiotensinogen Gene by Interleukin-6 Mol. Endocrinol., March 1, 2001; 15(3): 441 - 457. [Abstract] [Full Text]
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Z. Zhang and G. M. Fuller Interleukin 1beta inhibits interleukin 6-mediated rat gamma fibrinogen gene expression Blood, November 15, 2000; 96(10): 3466 - 3472. [Abstract] [Full Text] [PDF]
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 K L STREETZ, T LUEDDE, M P MANNS, and C TRAUTWEIN Interleukin 6 and liver regeneration Gut, August 1, 2000; 47(2): 309 - 312. [Full Text] [PDF]
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S. Aittomaki, M. Pesu, B. Groner, O. A. Janne, J. J. Palvimo, and O. Silvennoinen Cooperation Among Stat1, Glucocorticoid Receptor, and PU.1 in Transcriptional Activation of the High-Affinity Fc{gamma} Receptor I in Monocytes J. Immunol., June 1, 2000; 164(11): 5689 - 5697. [Abstract] [Full Text] [PDF]
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 T. Chen, L. H. Wang, and W. L. Farrar Interleukin 6 Activates Androgen Receptor-mediated Gene Expression through a Signal Transducer and Activator of Transcription 3-dependent Pathway in LNCaP Prostate Cancer Cells Cancer Res., April 1, 2000; 60(8): 2132 - 2135. [Abstract] [Full Text]
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P. L. Bergad, H. C. Towle, and S. A. Berry Yin-yang 1 and Glucocorticoid Receptor Participate in the Stat5-mediated Growth Hormone Response of the Serine Protease Inhibitor 2.1 Gene J. Biol. Chem., March 10, 2000; 275(11): 8114 - 8120. [Abstract] [Full Text] [PDF]
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 M.-D. T. Nguyen and P. J. Simpson-Haidaris Cell Type-Specific Regulation of Fibrinogen Expression in Lung Epithelial Cells by Dexamethasone and Interleukin-1beta Am. J. Respir. Cell Mol. Biol., February 1, 2000; 22(2): 209 - 217. [Abstract] [Full Text]
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J.-B. Demoulin, E. Van Roost, M. Stevens, B. Groner, and J.-C. Renauld Distinct Roles for STAT1, STAT3, and STAT5 in Differentiation Gene Induction and Apoptosis Inhibition by Interleukin-9 J. Biol. Chem., September 3, 1999; 274(36): 25855 - 25861. [Abstract] [Full Text] [PDF]
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N. Subramaniam, E. Treuter, and S. Okret Receptor Interacting Protein RIP140 Inhibits Both Positive and Negative Gene Regulation by Glucocorticoids J. Biol. Chem., June 18, 1999; 274(25): 18121 - 18127. [Abstract] [Full Text] [PDF]
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S. L. Wyszomierski, J. Yeh, and J. M. Rosen Glucocorticoid Receptor/Signal Transducer and Activator of Transcription 5 (STAT5) Interactions Enhance STAT5 Activation by Prolonging STAT5 DNA Binding and Tyrosine Phosphorylation Mol. Endocrinol., February 1, 1999; 13(2): 330 - 343. [Abstract] [Full Text]
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Y.-C. Zhou and D. J. Waxman Cross-talk between Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) and Peroxisome Proliferator-activated Receptor-alpha (PPARalpha ) Signaling Pathways. GROWTH HORMONE INHIBITION OF PPARalpha TRANSCRIPTIONAL ACTIVITY MEDIATED BY STAT5b J. Biol. Chem., January 29, 1999; 274(5): 2672 - 2681. [Abstract] [Full Text] [PDF]
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S. Gingras, R. Moriggl, B. Groner, and J. Simard Induction of 3{beta}-Hydroxysteroid Dehydrogenase/{Delta}5-{Delta}4 Isomerase Type 1 Gene Transcription in Human Breast Cancer Cell Lines and in Normal Mammary Epithelial Cells by Interleukin-4 and Interleukin-13 Mol. Endocrinol., January 1, 1999; 13(1): 66 - 81. [Abstract] [Full Text]
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R. Newton, J. Seybold, L. M. E. Kuitert, M. Bergmann, and P. J. Barnes Repression of Cyclooxygenase-2 and Prostaglandin E2 Release by Dexamethasone Occurs by Transcriptional and Post-transcriptional Mechanisms Involving Loss of Polyadenylated mRNA J. Biol. Chem., November 27, 1998; 273(48): 32312 - 32321. [Abstract] [Full Text] [PDF]
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J. K. Richer, C. A. Lange, N. G. Manning, G. Owen, R. Powell, and K. B. Horwitz Convergence of Progesterone with Growth Factor and Cytokine Signaling in Breast Cancer. PROGESTERONE RECEPTORS REGULATE SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION EXPRESSION AND ACTIVITY J. Biol. Chem., November 20, 1998; 273(47): 31317 - 31326. [Abstract] [Full Text] [PDF]
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N. Delesque-Touchard, S.-H. Park, and D. J. Waxman Synergistic Action of Hepatocyte Nuclear Factors 3 and 6 on CYP2C12 Gene Expression and Suppression by Growth Hormone-activated STAT5b. PROPOSED MODEL FOR FEMALE-SPECIFIC EXPRESSION OF CYP2C12 IN ADULT RAT LIVER J. Biol. Chem., October 27, 2000; 275(44): 34173 - 34182. [Abstract] [Full Text] [PDF]
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C. Widen, J. Zilliacus, J.-A. Gustafsson, and A.-C. Wikstrom Glucocorticoid Receptor Interaction with 14-3-3 and Raf-1, a Proposed Mechanism for Cross-talk of Two Signal Transduction Pathways J. Biol. Chem., December 8, 2000; 275(50): 39296 - 39301. [Abstract] [Full Text] [PDF]
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M. Niehof, K. Streetz, T. Rakemann, S. C. Bischoff, M. P. Manns, F. Horn, and C. Trautwein Interleukin-6-induced Tethering of STAT3 to the LAP/C/EBPbeta Promoter Suggests a New Mechanism of Transcriptional Regulation by STAT3 J. Biol. Chem., March 16, 2001; 276(12): 9016 - 9027. [Abstract] [Full Text] [PDF]
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J.-Y. Yoo, W. Wang, S. Desiderio, and D. Nathans Synergistic Activity of STAT3 and c-Jun at a Specific Array of DNA Elements in the alpha 2-Macroglobulin Promoter J. Biol. Chem., July 6, 2001; 276(28): 26421 - 26429. [Abstract] [Full Text] [PDF]
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J. Mullick, H. K. Anandatheerthavarada, G. Amuthan, S. V. Bhagwat, G. Biswas, V. Camasamudram, N. K. Bhat, S. E. P. Reddy, V. Rao, and N. G. Avadhani Physical Interaction and Functional Synergy between Glucocorticoid Receptor and Ets2 Proteins for Transcription Activation of the Rat Cytochrome P-450c27 Promoter J. Biol. Chem., May 18, 2001; 276(21): 18007 - 18017. [Abstract] [Full Text] [PDF]
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L. H. Wang, X. Y. Yang, K. Mihalic, W. Xiao, D. Li, and W. L. Farrar Activation of Estrogen Receptor Blocks Interleukin-6-inducible Cell Growth of Human Multiple Myeloma Involving Molecular Cross-talk between Estrogen Receptor and STAT3 Mediated by Co-regulator PIAS3 J. Biol. Chem., August 17, 2001; 276(34): 31839 - 31844. [Abstract] [Full Text] [PDF]
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