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Volume 271, Number 22, Issue of May 31, 1996 pp. 13221-13227
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

STAT3beta , a Splice Variant of Transcription Factor STAT3, Is a Dominant Negative Regulator of Transcription*

(Received for publication, November 27, 1995, and in revised form, February 28, 1996)

Eric Caldenhoven , Thamar B. van Dijk , Roberto Solari Dagger , John Armstrong Dagger , Jan A. M. Raaijmakers , Jan-Willem J. Lammers , Leo Koenderman and Rolf P. de Groot §

From the Department of Pulmonary Diseases, University Hospital Utrecht, Utrecht, The Netherlands, and the Dagger  Glaxo Wellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom

ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
FOOTNOTES
Acknowledgments
REFERENCES


ABSTRACT

The 89-kDa STAT3 protein is a latent transcription factor which is activated in response to cytokines (interleukin (IL)-5 and -6) and growth factors (epidermal growth factor). Binding of IL-5 to its specific receptor activates JAK2 which leads to the tyrosine phosphorylation of STAT3 proteins. Here we report the cloning of a cDNA encoding a variant of the transcription factor STAT3 (named STAT3beta ) which was isolated by screening an eosinophil cDNA library. Compared to wild-type STAT3, STAT3beta lacks an internal domain of 50 base pairs located near the C terminus. This splice product is a naturally occurring isoform of STAT3 and encodes a 80-kDa protein. We found by reconstitution of the human IL-5R in COS cells that like STAT3, STAT3beta is phosphorylated on tyrosine and binds to the pIRE from the ICAM-1 promoter after IL-5 stimulation. However, STAT3beta fails to activate a pIRE containing promoter in transient transfection assays. Instead, co-expression of STAT3beta inhibits the transactivation potential of STAT3. These results suggests that STAT3beta functions as a negative regulator of transcription.


INTRODUCTION

Stimulation of transcription factors by cytokines or growth factors is an important step in activating specific gene transcription leading to cell growth, differentiation, and many other cellular functions. To activate or repress transcription, transcription factors must be located in the nucleus, bind DNA, and interact with the basal transcriptional machinery. Most of these processes are achieved by phosphorylation of a transcription factor by protein kinases (1, 2). One of the earliest signaling events after cytokine stimulation is the activation of non-receptor protein tyrosine kinases, such as members of the Src and Janus kinase (JAK) families (3). Many individual cytokine receptors are linked to specific members of the JAK family which are activated after ligand binding. The activated JAK kinases phosphorylate and activate a novel family of transcription factors termed signal transducers and activators of transcription (STATs)1 (4). STAT proteins were first recognized in the interferon-alpha (IFN-alpha ) and beta signaling pathway. IFNalpha activates a latent cytoplasmic transcription factor complex interferon-stimulated gene factor 3 (5, 6, 7). This complex consists of a 48-kDa DNA-binding component, and the tyrosine-phosphorylated proteins STAT1alpha , STAT1beta , and STAT2 (8). By contrast, only STAT1alpha is tyrosine phosphorylated upon stimulation of cells with IFN-gamma (9). Until now, eight members of the STAT family: STAT1alpha , STAT1beta (6, 7), STAT2 (6), STAT3 (10, 11), STAT4 (12, 13), STAT5A, STAT5B (14, 15, 16), and STAT6 (17) have been identified and characterized. All the STATs are widely expressed in different cell types and tissues, except for STAT4, which is expressed predominantly in testis and in cells of hematopoietic origin. Phosphorylation on tyrosine of the STAT proteins is required for dimerization, DNA-binding, and the activation of transcription (18, 8). However, STAT1beta , which is a splice product of STAT1alpha and lacks 38 amino acids of the carboxyl terminus, is phosphorylated on tyrosine but is transcriptionally inactive (18). Furthermore, we and others found that H7, which is a serine/threonine kinase inhibitor, blocked the transactivation potential of STAT1 and/or STAT3 (19, 20, 21, 22). These results suggest that phosphorylation of serine residues in STAT1 and STAT3 are necessary for the transcriptional activity of these proteins.

Cytokines such as interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony stimulating factor (GM-CSF) play an important role in hematopoiesis (23, 24, 25). Although IL-3 and GM-CSF also have effects on other hematopoietic lineages (25, 26), the actions of IL-5 in humans are restricted to eosinophils and basophils, since the IL-5 receptor (IL-5R) is only expressed on these cell types (27, 28). IL-5 is essential for eosinophil differentiation (29, 30) and plays an important role in functioning of mature eosinophils and basophils (31, 32, 33, 34, 35). The IL-5R is composed of a unique alpha subunit associated with a beta c subunit that is identical to those of the receptors for IL-3 and GM-CSF (36). We and others have shown that JAK2 is activated by IL-3, IL-5, and GM-CSF (37, 38), and constitutively associates with the membrane-proximal region of the beta c subunit (39). Recently, we have described that STAT3 activity increases in response to interleukin-5 (IL-5) in both BaF3 and COS cells ectopically expressing the hIL-5 receptor (IL-5R) (40). Although STAT3 is tyrosine phosphorylated and activated by IL-5 in these cells, it was only activated to a very low extent in mature eosinophils. Based on this and the observation that multiple STATs are activated by IL-5 in eosinophils (37), we screened an eosinophil cDNA library to identify IL-5 induced novel STAT cDNAs.

Here we report the cloning and characterization of a STAT3 variant which we isolated from the eosinophil cDNA library. This protein (STAT3beta ) is a truncated form of STAT3 which is probably generated by differential splicing. STAT3 and STAT3beta protein are co-expressed in various cell types. We found that STAT3beta is rapidly phosphorylated on tyrosine upon IL-5 stimulation of COS cells. However, although STAT3beta efficiently binds to the palindromic IL-6/IFNgamma response element (pIRE) from the intercellular adhesion molecule 1 (ICAM-1) promoter, it is unable to activate a promoter containing this pIRE element. We also demonstrate that STAT3beta is a strong dominant inhibitor of transcription.


MATERIALS AND METHODS

Eosinophil cDNA Library Construction

Human eosinophils were isolated from two hyper-eosinophilic individuals according to a slight modification (41) of the method described previously (42). The purity of the eosinophils collected was at least 95% as determined by histochemical staining of cytospins with May-Grunwald-Giemsa stain. Viability determined by trypan blue exclusion was more than 98%. Total RNA was extracted from 1 × 108 eosinophils using an Rnaid kit according to the manufacturers instructions (BIO 101 Inc.). Poly(A)+ mRNA was extracted by oligo(dT) affinity purification using Dynabeads Oligo(dT)25 (Dynal, Norway). This mRNA was used to construct an EcoRI/XhoI directional cDNA library in the lambda ZAPII vector as described by the manufacturer (Stratagene). The library contained greater than 2 × 106 primary recombinants with a background of less than 10%. The average insert size was approximately 1.5 kilobase and the largest inserts were estimated to be greater than 5 kilobases.

Cell Culture, Reagents, and Antibodies

Monkey COS-1 cells were cultured in Dulbecco's modified Eagle's medium (Life Technologies, Inc.) supplemented with 10% heat inactivated fetal calf serum. Human IL-5 (hIL-5) was a kind gift of Dr. D. Fattah (Glaxo Wellcome, Stevenage). The anti-phosphotyrosine monoclonal antibody 4G10 was obtained from UBI (Lake Placid, NY). The monoclonal antibody directed against STAT1alpha /beta was purchased from Transduction Laboratories (Lexington, KY). The STAT3 rabbit polyclonal antibodies K15 (directed against amino acids 626-640) and C20 (directed against amino acids 750-769) were obtained from Santa Cruz Biotechnology (Santa Cruz, CA).

Synthetic Oligonucleotides and Plasmid Construction

Oligonucleotides with the following sequence were used in this study (only the top strand is shown): the human ICAM-1 pIRE, 5'-AGCTTAGGTTTCCGGGAAAGCAC-3'. The 2xpIREtkluc and pICAM1-339 reporter constructs has been described by Caldenhoven et al. (43) and the pSV-lacZ expression vector by Shen et al. (44). pSGhIL5Ralpha was constructed by inserting the cDNA for the human IL-5alpha receptor from pBKhIL5Ralpha (45) into the Not/KpnI sites of pSG513. pSGhIL5Rbeta was constructed by inserting the cDNA for the human beta c subunit from pSV532 (36) into the EcoRI sites of pSG513. The expression vectors containing the cDNAs for hSTAT1, mSTAT3, and hSTAT4 were provided by Dr. James E. Darnell, Jr. (7, 11). The hSTAT6 cDNA was provided by Dr. Steven L. McKnight (17). Full-length STAT cDNAs were used for the screening of the cDNA library. The hSTAT3 and hSTAT3beta were isolated from the eosinophil cDNA library and cloned into the EcoRI site of PSG513.

Transient Transfections

For transfection experiments, COS cells were split 1:3 in 6-well plates (Costar), and 2 h later the cells were transfected with 10-20 µg of supercoiled plasmid DNA by the calcium phosphate coprecipitation technique (46). Following 16-20 h exposure to the calcium-phosphate precipitate, medium was refreshed, and cells were incubated for 16 h with IL-5. Transfected cells were subsequently harvested for luciferase assay (47) and lacZ determination (48).

Gel Retardation Assay

Nuclear extracts were prepared from unstimulated and IL-5 stimulated COS cells following a previously described procedure (49). Oligonucleotides were labeled by filling in the cohesive ends with [alpha -32P]dCTP using Klenow fragment of DNA polymerase I. Gel retardation assays were carried out according to published procedures with slight modifications (5). Briefly, nuclear extracts (10 µg) were incubated in a final volume of 20 µl, containing 10 mM HEPES, pH 7.8, 50 mM KCl, 1 mM EDTA, 5 mM MgCl2, 10% (v/v) glycerol, 5 mM dithiothreitol, 2 µg of poly(dI-dC) (Pharmacia), 20 µg of bovine serum albumin, and 1.0 ng of 32P-labeled ICAM1-pIRE oligonucleotide for 20 min at room temperature. In competition experiments, extracts were incubated for 5 min with the indicated molar excess of unlabeled oligonucleotide prior to the addition of labeled oligonucleotide. Supershift analysis were performed by preincubating 10 µg of nuclear extract with 1 µl (1 µg) of anti-STAT3 antibody for 30 min on ice prior to addition of the binding buffer and 32P-labeled probe.

Immunoprecipitation and Western Blotting

Unstimulated and IL-5 stimulated COS cells were incubated with RIPA lysis buffer (20 mM Tris, pH 7.4, 150 mM NaCl, 1% Nonidet P-40, 0.1% SDS, 0.5% sodium deoxycholate, 5 mM EDTA, Na3VO4, 10 mg/ml aprotinine, 1 mM phenylmethylsulfonyl fluoride, 1 mM leupeptin) for 15 min on ice. The lysate was centrifuged to remove DNA and cellular debris. The cell lysates were incubated with the anti-STAT3 polyclonal antibody for 1 h at 4 °C. Immune complexes were then precipitated with protein A-Sepharose for 1 h at 4 °C, washed three times with lysis buffer, and boiled in 1 × Laemmli's sample buffer. The proteins were electrophoresed on a SDS-polyacrylamide gel and transferred to nitrocellulose membrane. After blocking in TBST (150 mM NaCl, 10 mM Tris, pH 8.0, 0.3% Tween 20) with 5% bovine serum albumin, the membrane was either incubated with the anti-phosphotyrosine (4G10) monoclonal antibody, or with the polyclonal anti-STAT3 antibody. After washing three times with TBST the membrane was incubated for 1 h with peroxidase-conjugated rabbit anti-mouse or swine anti-rabbit antibodies, respectively. In both cases the membrane was washed five times with TBST and immunoprecipitated proteins were visualized with enhanced chemiluminescence (ECL, Amersham). Between the incubation with 4G10 and STAT3 antibodies the membrane was stripped with 1% SDS, 30 mM Tris, pH 8.0, 50 mM beta -mercaptoethanol for 2 × 15 min at 55 °C.


RESULTS

Isolation of a Short Form of STAT3

In order to identify new STAT proteins expressed in eosinophils that may play a role in IL-5 signaling, an eosinophil cDNA library was screened with a labeled probe containing the full-length STAT cDNAs of hSTAT1, mSTAT3, hSTAT4, and hSTAT6. After low stringency screening of the cDNA library, several positive phage clones were isolated. The inserts of these clones were characterized by Southern hybridization and sequencing. All the isolated clones encode known STAT proteins including hSTAT3, hSTAT4, and hSTAT6. However, one of the STAT3 positive cDNA clones showed a different restriction pattern compared to the wild type STAT3 cDNA. Sequencing of this clone revealed that it is almost identical to STAT3 but lacks an internal part of 50 base pairs, covering nucleotides 2145-2195 near the COOH terminus (Fig. 1A). This deletion removes codons 716 to 732 and in addition causes a shift in the open reading frame resulting in the formation of a stop codon after 7 amino acids (Fig. 1B). This truncated STAT3 mRNA encodes a protein consisting of the first 715 amino acids of STAT3 plus an additional 7 unique amino acids. Comparison of the amino acids in the carboxyl-terminal region shows that this truncated STAT3 protein contains the tyrosine phosphorylation site at position 704, but lacks the conserved PMSP sequence which is a substrate for a serine kinase (50). Based on published work (7) identifying a splice variant of STAT1 named STAT1beta , it is likely that the truncated form of STAT3 results from an alternative splicing event as well. We therefore designated the STAT3 clone with this internal deletion as STAT3beta . To determine whether this isoform is not a cloning artifact we performed a polymerase chain reaction experiment with internal primers depicted in Fig. 1A on mRNA from the cell types mentioned below. As expected, two polymerase chain reaction products were formed a 300-base pair fragment and a minor 250-base pair fragment (data not shown). Sequencing revealed that these DNA fragments corresponds to the internal regions of STAT3 (300 base pairs) and STAT3beta (250 base pairs). Additional evidence that this isoform is not a cloning artifact comes from the independent isolation of this cDNA by Schaefer et al. (51), who isolated this cDNA via a two hybrid screen with a N-terminal segment of c-Jun.


Fig. 1. Nucleotide and amino acid sequence of the COOH-terminal regions of human STAT3 and STAT3beta . A, STAT3 and STAT3beta cDNAs were isolated from a human eosinophil cDNA library, subcloned, and sequenced. As can be observed, STAT3beta contains an internal deletion of 50 nucleotides. The positions of the stop codons used in STAT3 and STAT3beta and the primers used for the detection of STAT3 and STAT3beta mRNA are indicated. B, schematic representation of the amino acid sequences of STAT3 and STAT3beta around the internal deletion. Positions of the Src homology 2 (SH2), SH3, and tyrosine phosphorylation (Tyr704) domains are indicated. Due to the deletion in STAT3beta , the reading frame is switched and a stop codon is generated 7 amino acids downstream of the internal deletion.

STAT3beta Is Expressed in Different Cell Types

To investigate the existence of the STAT3beta protein and to establish its tissue distribution, we performed a STAT3 immunoprecipitation from different cell types. For this purpose, cell lysates were prepared from U937, HL-60, BaF3 cells, eosinophils, COS cells, and COS cells transfected with the cDNA encoding for STAT3beta (COS/STAT3beta ). The proteins were precipitated with a specific STAT3 antibody directed against residues 626-640 and immunoblotted with this STAT3 antibody. Fig. 2A shows that untransfected COS cells express only a low amount of the 89-kDa STAT3 protein. However, overexpressing STAT3beta in COS cells results in the appearance of an 80-kDa protein which comigrated with an endogenously expressed 80-kDa protein in the other cell types analyzed with the STAT3 antibody. The expression of this 80-kDa protein varies between the different cell types studied (Fig. 2A). This 80-kDa protein was also found in blood monocytes, lymphocytes, and neutrophils (data not shown). To ascertain that the endogenously expressed 80-kDa protein was STAT3beta , we precipitated the proteins with a STAT3 antibody directed against amino acids 750-769, a domain lacking in the STAT3beta protein. Using this antibody we detect only the 89-kDa wild type STAT3 protein in COS/STAT3, COS/STAT3beta , U937, and HL-60 cells (Fig. 2C, lanes 5-8). When proteins from these cells were precipitated with STAT3 antibodies directed against residues 629-640, two STAT3 proteins appeared of 89 and 80 kDa, except for the COS/STAT3 cells which shows only the wild type STAT3 (Fig. 2C, lanes 1-4). We therefore conclude that the endogenously expressed 80-kDa protein in primary cells as well as in the cell lines is likely to be STAT3beta since it is not recognized by an antibody against the N terminus which is lacking from STAT3beta .


Fig. 2. Expression and tyrosine phosphorylation of the STAT3beta protein. A, whole cell extracts from COS (lane 1), COS transfected with STAT3beta (lane 2), BaF3 (lane 3), HL-60 (lane 4), U937 (lane 5), and eosinophils (lane 6) were monitored for the presence of STAT3 and STAT3beta by immunoprecipitation with a STAT3 specific antibody (amino acids 629-640) followed by Western blotting with the same antibody. The protein of about 89 kDa represents STAT3, while the smaller protein (80 kDa) is STAT3beta . STAT3 and STAT3beta are co-expressed in different cell types, although at different ratios. B, COS cells were transfected with the IL-5R alpha and beta cDNAs together with the pSG5 expression vector (lanes 1 and 2), STAT3 (lanes 3 and 4), or STAT3beta (lanes 5 and 6). 48 h after transfection, cells received IL-5 for 15 min (lanes 2, 4, and 6), after which cells were lyzed and STAT3 was immunoprecipitated. The blot was first probed with an anti-phosphotyrosine antibody (upper panel), stripped, and probed with the STAT3 antibody (lower panel). IL-5 causes a strong increase in tyrosine phosphorylation of both STAT3 and STAT3beta . The faster migrating bands observed in lanes 3 and 4 (lower panel) are sometimes observed, and are probably the result of degradation of STAT3. C, whole cell extracts from COS cells transfected with STAT3 (lanes 1 and 5), or STAT3b (lanes 2 and 6), U937 (lane 3 and 7), and HL-60 cells (lanes 4 and 8) were immunoprecipitated with a STAT3 antibody (629-640) (lanes 1-4) or a STAT3 antibody (amino acids 750-769) (lanes 5-8) and blotted with STAT3 antibody (629-640). The endogenously expressed 80-kDa protein is likely to be STAT3beta .

Tyrosine Phosphorylation and DNA Binding of STAT3beta

We have previously shown that STAT3 becomes tyrosine phosphorylated after IL-5 treatment in both BaF3 and COS cells (40). Since STAT3beta still retains the tyrosine residue necessary for STAT3 activation, we were interested whether STAT3beta is phosphorylated on tyrosine after IL-5 stimulation. To test this prediction we co-transfected COS cells with expression vectors encoding both subunits of the IL-5 receptor (IL-5Ralpha and IL-5Rbeta ), together with STAT3 or STAT3beta . We immunoprecipitated STAT3 from unstimulated and IL-5 stimulated COS cells and tyrosine phosphorylation was then monitored by Western blotting using the anti-phosphotyrosine antibody 4G10. Fig. 2B shows that both wild-type STAT3 and STAT3beta are phosphorylated on tyrosine after IL-5 stimulation. However, although the expression of STAT3beta protein is less then wild-type STAT3, the amount of tyrosine phosphorylation is higher. In addition, even in the absence of IL-5 signaling, we detected some basal level tyrosine phosphorylation of STAT3beta , which we have never observed with STAT3.

Tyrosine phosphorylation of STAT proteins leads to dimerization, translocation to the nucleus, and binding to specific binding sites on the DNA. We therefore tested the ability of STAT3beta to bind DNA and compared this with wild-type STAT3. COS cells expressing the IL-5R and either wild-type STAT3 or STAT3beta were treated with IL-5 for 15 min and nuclear extracts were prepared. When these nuclear extracts were assayed in a gel retardation assay for binding to a 32P-labeled ICAM-1 pIRE, an increase in STAT3 and STAT3beta binding was observed after IL-5 treatment (Fig. 3). Unexpectedly, however, the STAT3 complex migrated faster than the STAT3beta complex. The STAT3beta complex is specific because an anti-STAT3 antibody produced a supershift, while STAT1 antiserum had no effect on this complex. Furthermore, the DNA binding activity of STAT3beta is higher than STAT3, which is probably due to the higher amount of tyrosine-phosphorylated STAT3beta proteins observed (Fig. 2B). In addition, we observed some basal level DNA binding activity by STAT3beta in unstimulated cells, which is in agreement with the observed tyrosine phosphorylation in unstimulated cells (Fig. 2B). We can conclude that both wild-type STAT3 and STAT3beta are tyrosine phosphorylated after IL-5 stimulation which results in an increase in DNA binding of both proteins.


Fig. 3. Both STAT3 and STAT3beta bind to DNA after activation by IL-5. The hIL-5 receptor and STAT3 or STAT3beta were expressed in COS cells. These cells were either untreated or treated for 30 min with IL-5, after which nuclear extracts were prepared. Nuclear extract were assayed for binding to the 32P-labeled ICAM-1 pIRE in band shift experiments. For competition experiments, extracts were preincubated for 5 min with a 50-fold molar excess of unlabeled oligonucleotide as indicated. For supershift analysis, the extracts were incubated with either anti-STAT1alpha or anti-STAT3 antibodies for 30 min before the addition of the 32P-labeled ICAM-1 pIRE. IL-5 clearly induces binding of STAT3 and STAT3beta to the ICAM-1 pIRE.

STAT3beta Acts as a Dominant Transcriptional Repressor

To compare the transcriptional activity of STAT3 with STAT3beta , we transiently transfected COS cells with expression vectors for the IL-5R, wild-type STAT3, or STAT3beta together with a luciferase reporter construct, containing two copies of the pIRE from the ICAM-1 promoter. Transfection of the wild-type STAT3 cDNA shows an IL-5 dependent 15-fold increase in luciferase activity (Fig. 4A). By contrast, transfection of STAT3beta gave almost no increase in luciferase activity after IL-5 stimulation. An explanation for this could be that the region which is absent from STAT3beta contains a domain important for transactivation. We further determined the effect of STAT3beta on transactivation mediated by STAT3. We tested this by co-transfection of an increasing amount of STAT3beta expression vector together with a constant amount of STAT3 expression vector. The total amount of DNA was kept constant by adding the pSG5 vector. In this experiment we see that transactivation by STAT3 is already inhibited by low amounts of STAT3beta (Fig. 4B). Western blotting indicated that STAT3beta expression did not alter the level of STAT3 (data not shown). These results implicate that STAT3beta can act as a dominant negative regulator of STAT3-mediated transcription. To make sure that this dominant effect of STAT3beta also occurs on a natural promoter we used the ICAM-1 promoter containing the IRE in transient transfections experiments. COS cells were transfected with this reporter construct together with STAT3, STAT3beta , or a combination of both STAT proteins and stimulated with IL-5. We found that although STAT3 is an activator of the ICAM-I promoter, STAT3beta is transcriptionally inactive on the ICAM-1 promoter and acts as a dominant negative regulator of STAT3-mediated transcription. (Fig. 4C).


Fig. 4. STAT3beta is a dominant negative regulator of transcription. A, COS cells were transfected with the IL-5R, a pIRE containing luciferase reporter construct and STAT3 or STAT3beta . 24 h post-transfection, cells were stimulated for 16 h with IL-5 (10-10 M), after which transcriptional activation was measured by assaying for luciferase activity. Fold induction represents luciferase activity in IL-5-treated cells compared to untreated cells, and is the mean of three independent experiments. STAT3beta is unable to support IL-5 induced activation of the pIRE reporter construct. B, COS cells were transfected as described in A with different amounts of STAT3 and STAT3beta as indicated. Low amounts of STAT3beta already significantly decrease trans-activation by STAT3, while high amounts of STAT3beta completely inhibit STAT3-mediated transcriptional activation. C, COS cells were transfected as described in A and B. We used the ICAM-1 promoter as a luciferase reporter construct (pIC-339luc). STAT3beta is also transcriptionally inactive on the natural ICAM-1 promoter.

Since all STAT proteins form homo- or heterodimers after phosphorylation on tyrosine, a mechanism for the inhibition could be that STAT3 and STAT3beta form heterodimers which are unable or less able to mediate transactivation. To investigate this, we prepared nuclear extracts from IL-5-treated COS cells transfected with STAT3 and increasing amounts of STAT3beta . We assayed these nuclear extracts for binding to the ICAM-1 pIRE and performed a long run gel retardation to resolve the different complexes. As we already observed, the affinity of STAT3beta homodimers (Fig. 5A, lane 6) to the pIRE is higher then the binding of STAT3 homodimers (lane 1). Interestingly, an intermediate complex C2 was observed when STAT3beta is co-transfected together with STAT3, which is likely to consist of a STAT3/STAT3beta heterodimer. To resolve all three DNA-binding complexes, lanes 2-7 were exposed less than lane 1. We also identified the components in these complexes using two specific STAT3 antibodies, one directed against residues 629-640 supershifting both STAT3 and STAT3beta (Fig. 5B, lanes 2 and 5), the other against residues 750-769 which recognized only STAT3 (lanes 3 and 6). We further show that the STAT3 (750-769) antibody which recognizes only STAT3 supershifted only the STAT3/STAT3beta heterodimer and had no effect on the STAT3beta homodimer (lane 9). These results clearly demonstrate that STAT3 and STAT3beta form heterodimeric DNA-binding complexes.


Fig. 5. Heterodimerization between STAT3 and STAT3beta . A, COS cells were transfected with the IL-5R and different amounts of STAT3 and STAT3beta . 48 h after transfection, cells were treated with IL-5 for 15 min and DNA binding activity was monitored using a 32P-labeled pIRE. Co-expression of STAT3 (C3) and STAT3beta (C1) results in the formation of a heterodimeric complex (C2). B, nuclear extracts from COS cells transfected with STAT3, STAT3beta , or STAT3/STAT3beta , stimulated for 15 min with IL-5 were preincubated with two different STAT3 antibodies STAT3 Ab (629-640) and STAT3 Ab (750-769). DNA binding activity was monitored using a 32P-pIRE. These data clearly show the formation of STAT3beta homodimers and STAT3/STAT3beta heterodimers.


DISCUSSION

STAT proteins are a rapidly expanding family of transcription factors that transduce short-term cytoplasmic signals elicited by polypeptide growth factors and cytokines into long-term changes in gene expression (52). Here, the cloning and characterization of a novel isoform of the STAT3 transcription factor is reported, which is named STAT3beta in analogy with STAT1alpha /STAT1beta . Although STAT3beta is phosphorylated on tyrosine upon IL-5 stimulation and binds efficiently to the pIRE from the ICAM-1 promoter, it fails to support pIRE-driven transcription in IL-5-stimulated cells. Moreover, STAT3beta is an efficient dominant negative regulator of STAT3-mediated transcription.

Differential splicing in the STAT family is not unprecedented. Schindler et al. (7) have shown that the STAT1 gene encodes at least two different proteins, STAT1alpha and STAT1beta , that are generated by alternative splicing. Like STAT3beta , STAT1beta can be phosphorylated on tyrosine but fails to activate transcription (18). However, whether STAT1beta can act as a dominant negative regulator of STAT1alpha was never investigated. The splicing event occurs at a highly homologous position in STAT1 and STAT3 (22, 52), suggesting that STAT1 and STAT3 might have a conserved exonic organization as was previously demonstrated for STAT1 and STAT2 (53). Verification of this hypothesis, however, awaits deciphering of the precise exonic structure of the STAT3 gene.

It was previously suggested that besides tyrosine phosphorylation, serine phosphorylation might play a crucial role in gene regulation by STAT proteins. The serine/threonine kinase inhibitor H7 was shown to be able to block transcriptional regulation by STAT1 and STAT3 (19, 20). Similarly, Boulton et al. (22) reported an H-7 sensitive phosphorylation of STAT3, but not STAT1. In addition, it was shown that serine phosphorylation might be necessary for DNA binding by STAT3 homodimers, but not by STAT1 homo- or STAT1/STAT3 heterodimers (21). In this paper we have shown that STAT3beta is efficiently phosphorylated on tyrosine upon IL-5 stimulation (Fig. 2B), which leads to a strong increase in DNA binding by STAT3beta (Fig. 3). However, in contrast to STAT3, STAT3beta is unable to mediate transactivation via a pIRE containing promoter. Examination of the amino acids deleted from STAT3beta shows the presence of a large number of serine and threonine residues, of which serine 727 is conserved between STAT1alpha , STAT3, STAT4, and STAT5, but not STAT1beta . Interestingly, this serine lies within a highly conserved PMSP sequence that was previously shown to be a microtubule-associated protein kinase recognition sequence (50). The importance of this serine was very recently shown by Wen et al. (20), who showed that this serine is inducibly phosphorylated in both STAT1alpha and STAT3. Furthermore, when they mutated this serine to alanine (STAT1alpha S), trans-activation was decreased 5-fold, although STAT1alpha S was still able to support an IFNgamma -induced 5-fold increase in transcription, whereas STAT1beta is completely inactive in this system (20). Similarly, mutation of serine 727 in STAT3 also decreased transactivation about 2.5-fold, although the mutant was still able to support an 8-fold induction of INFgamma activation site-mediated transcription (20). The lack of serine 727 in STAT3beta explains some, but not all of the results presented in this paper. STAT3beta is completely unable to mediate transcriptional activation in COS cells (Fig. 4A), whereas STAT3 with the 727 mutation is still a relatively good trans-activator in U3A cells (20). This might be caused by cell type-specific differences between COS and U3A. Alternatively, there might be more phosphorylated residues present in the region that is deleted from STAT3beta which contribute to transcriptional activation. Finally, the basal level tyrosine phosphorylation (Fig. 2B) and DNA binding (Fig. 3) observed with STAT3beta in unstimulated COS cells represents a striking difference with both STAT3-727 and STAT1beta . Although we do not have any experimental data to support this hypothesis, this observation suggests the presence of a domain in the COOH-terminal 55 amino acids of STAT3 that is somehow able to block STAT3 phosphorylation by JAK kinases in unstimulated cells.

The observation that STAT3beta is transcriptionally inactive is in contrast with data published recently by Schaefer et al. (51). They have identified STAT3beta via a two-hybrid system as a protein capable of binding to the NH2-terminal part of the c-Jun protein. Furthermore, they have shown that STAT3beta is transcriptionally active on the alpha 2-macroglobulin promoter in the absence of added cytokines. This constitutive transactivation potential is consistent with our own results showing a constitutive tyrosine phosphorylation of STAT3beta . The opposite effects found on the transactivation potential of STAT3beta can be due to the promoter targets used in both studies. We have used an artificial reporter containing only STAT binding sites and the natural ICAM-I promoter, while the alpha 2-macroglobulin promoter used by Schaefer et al. (51) contains a STAT binding site closely linked to a Jun binding site. Occupation of the Jun binding site by members of the Jun/Fos family might somehow alter the transcription activation potential of STAT3beta . Opposite effects by a single transcription factor on different promoters has also been described for hormone receptors which can either activate or repress gene transcription depending on the promoter (54). Further experiments are required for deciphering the different roles that STAT3beta might have in transcriptional regulation.

The observed dominant negative effect of STAT3beta over STAT3 might be caused by two different mechanisms. One possibility might be that STAT3beta homodimers have a higher affinity for the pIRE, and therefore occupy these sites on the DNA even when STAT3 is more abundantly expressed. Indeed, we have observed that while STAT3beta expression was 2-fold lower in transfected COS cells (Fig. 2B), DNA binding by STAT3beta was 2-3-fold higher compared to STAT3 (Fig. 3). This is likely to be caused by the higher extent of tyrosine phosphorylation observed in STAT3beta (Fig. 2B). On the other hand, since dimerization of STAT proteins is required for the formation of transcriptionally active DNA binding complexes (52), heterodimerization between STAT3 and STAT3beta might be involved in the dominant negative effect. In Fig. 5 we show that STAT3 and STAT3beta indeed form a heterodimer. Moreover, even a small amount of STAT3beta is sufficient to disrupt all the STAT3 homodimers and drive them into STAT3/STAT3beta heterodimers. However, at this ratio between STAT3 and STAT3beta (6:2 µg), we still observe transcriptional activation of a pIRE containing plasmid (Fig. 4B), although it is 50% less compared to STAT3 alone. This suggests that the STAT3/STAT3beta heterodimer is able to support IL-5 induced transcription, albeit with a lower efficiency than the STAT3 homodimer. Taken together, the observed dominant negative effect of STAT3beta is likely to be caused by a combination of transcriptionally inactive STAT3beta homodimers with high DNA binding activity and STAT3beta /STAT3 heterodimers which are weak transcriptional activators. The generation of transcriptional activators and repressors from the same gene is not unprecedented (55). mTFE3, a murine transcription factor involved in the activation of immunoglobulin heavy chain transcription, is turned into a repressor by a splicing event that removes part of the activation domain (56). Similarly, a splicing event removing part of the activation domain of FosB results in the expression of Delta FosB, an inhibitor of Fos/Jun transcriptional activity (57), while splicing out the activation domains of CREMtau generates CREMalpha , which, despite the fact that it retains the protein kinase A phosphoacceptor site, is an efficient antagonist of cAMP-induced transcription (58, 59). The use of alternative initiation codons can also be a mechanism to generate activators and repressors from the same mRNA, as was reported for liver-enriched activator protein and liver-enriched inhibitory protein (60) and for CREM and S-CREM (61). In this paper we report that an alternative splicing event removing 55 amino acids from the COOH terminus of STAT3 generates STAT3beta , an efficient repressor of STAT3-mediated transcription. Although it is likely that the removal of serine 727 contributes to this switch from activator to repressor, the precise molecular mechanism awaits further mutational analysis of STAT3, since the nature of the activation domain of STAT3 remains to be elucidated. As was described previously for mTFE3, FosB, CREM, and liver-enriched activator protein (55), we found that the activator STAT3 and the repressor STAT3beta are co-expressed in a wide variety of cell types (Fig. 2A), although the ratio between the two differs between cell types studied. Cell type-specific differences in the ratio between STAT3 and STAT3beta could lead to differences in the response to IL-5 or other activators of STAT3. It would therefore be interesting to determine the mechanism by which the ratio between STAT3 and STAT3beta is modulated in a cell type-specific manner. Another challenge will be to find physiological processes in which the ratio between STAT3 and STAT3beta is altered in a temporal or spatial fashion due to signal transduction dependent alternative splicing.


FOOTNOTES

*   This work was supported by a research grant from Glaxo bv. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) U30709[GenBank].


§   To whom correspondence should be addressed: Dept. of Pulmonary Diseases, G03.550, University Hospital Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Tel.: 31-30-507134; Fax: 31-30-542155.
1   The abbreviations used are: STAT, signal transducer and activator of transcription; JAK, Janus kinase; IFN, interferon; IL-5, interleukin-5; IL-5R, interleukin-5 receptor; GM-CSF, granulocyte macrophage-colony stimulating factor; IRE, interferon/IL-6-responsive element; pIRE, palindromic IL-6/IFNgamma response element; ICAM-1, intercellular adhesion molecule-1; CREM, cAMP-responsive element modulator; S-CREM, short CREM.

Acknowledgments

We thank James E. Darnell, Jr., and Jan Tavenier for the kind gift of plasmids. We further thank Dilnya Fattah for hIL-5 and Paul Coffer for critically reading the manuscript.


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SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION: INSIGHTS INTO THE MOLECULAR BASIS OF ORAL CANCER
Critical Reviews in Oral Biology & Medicine, September 1, 2004; 15(5): 298 - 307.
[Abstract] [Full Text] [PDF]


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Cardiovasc ResHome page
V. P.M van Empel and L. J De Windt
Myocyte hypertrophy and apoptosis: a balancing act
Cardiovasc Res, August 15, 2004; 63(3): 487 - 499.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
M. Severgnini, S. Takahashi, L. M. Rozo, R. J. Homer, C. Kuhn, J. W. Jhung, G. Perides, M. Steer, P. M. Hassoun, B. L. Fanburg, et al.
Activation of the STAT pathway in acute lung injury
Am J Physiol Lung Cell Mol Physiol, June 1, 2004; 286(6): L1282 - L1292.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
H. Shao, X. Xu, M.-A. A. Mastrangelo, N. Jing, R. G. Cook, G. B. Legge, and D. J. Tweardy
Structural Requirements for Signal Transducer and Activator of Transcription 3 Binding to Phosphotyrosine Ligands Containing the YXXQ Motif
J. Biol. Chem., April 30, 2004; 279(18): 18967 - 18973.
[Abstract] [Full Text] [PDF]


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J. Virol.Home page
A. V. Chee and B. Roizman
Herpes Simplex Virus 1 Gene Products Occlude the Interferon Signaling Pathway at Multiple Sites
J. Virol., April 15, 2004; 78(8): 4185 - 4196.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
J.-P. Herbeuval, E. Lelievre, C. Lambert, M. Dy, and C. Genin
Recruitment of STAT3 for Production of IL-10 by Colon Carcinoma Cells Induced by Macrophage-Derived IL-6
J. Immunol., April 1, 2004; 172(7): 4630 - 4636.
[Abstract] [Full Text] [PDF]


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J. Am. Soc. Nephrol.Home page
Z. Yu and B. C. Kone
The STAT3 DNA-Binding Domain Mediates Interaction with NF-{kappa}B p65 and Inducible Nitric Oxide Synthase Transrepression in Mesangial Cells
J. Am. Soc. Nephrol., March 1, 2004; 15(3): 585 - 591.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Gastrointest. Liver Physiol.Home page
C. Hierholzer, J. C. Kalff, T. R. Billiar, A. J. Bauer, D. J. Tweardy, and B. G. Harbrecht
Induced nitric oxide promotes intestinal inflammation following hemorrhagic shock
Am J Physiol Gastrointest Liver Physiol, February 1, 2004; 286(2): G225 - G233.
[Abstract] [Full Text] [PDF]


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Molecular Cancer TherapeuticsHome page
B. E. Barton, J. G. Karras, T. F. Murphy, A. Barton, and H. F-S. Huang
Signal transducer and activator of transcription 3 (STAT3) activation in prostate cancer: Direct STAT3 inhibition induces apoptosis in prostate cancer lines
Mol. Cancer Ther., January 1, 2004; 3(1): 11 - 20.
[Abstract] [Full Text]


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Cancer Res.Home page
H. Shao, H. Y. Cheng, R. G. Cook, and D. J. Tweardy
Identification and Characterization of Signal Transducer and Activator of Transcription 3 Recruitment Sites within the Epidermal Growth Factor Receptor
Cancer Res., July 15, 2003; 63(14): 3923 - 3930.
[Abstract] [Full Text] [PDF]


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BloodHome page
A. Lundquist, B. Barre, F. Bienvenu, J. Hermann, S. Avril, and O. Coqueret
Kaposi sarcoma-associated viral cyclin K overrides cell growth inhibition mediated by oncostatin M through STAT3 inhibition
Blood, May 15, 2003; 101(10): 4070 - 4077.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
E. B. Kabotyanski and J. M. Rosen
Signal Transduction Pathways Regulated by Prolactin and Src Result in Different Conformations of Activated Stat5b
J. Biol. Chem., May 2, 2003; 278(19): 17218 - 17227.
[Abstract] [Full Text] [PDF]


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BloodHome page
M. Benekli, M. R. Baer, H. Baumann, and M. Wetzler
Signal transducer and activator of transcription proteins in leukemias
Blood, April 15, 2003; 101(8): 2940 - 2954.
[Abstract] [Full Text] [PDF]


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Cardiovasc ResHome page
V. P.M van Empel and L. J De Windt
Human heart failure: our current STATus of knowledge
Cardiovasc Res, February 1, 2003; 57(2): 294 - 297.
[Full Text] [PDF]


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Cardiovasc ResHome page
D. C.H Ng, N. W Court, C. G dos Remedios, and M. A Bogoyevitch
Activation of signal transducer and activator of transcription (STAT) pathways in failing human hearts
Cardiovasc Res, February 1, 2003; 57(2): 333 - 346.
[Abstract] [Full Text] [PDF]


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Mol. Endocrinol.Home page
L. Bjornstrom and M. Sjoberg
Signal Transducers and Activators of Transcription as Downstream Targets of Nongenomic Estrogen Receptor Actions
Mol. Endocrinol., October 1, 2002; 16(10): 2202 - 2214.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
M. A. Sherman, D. R. Powell, and M. A. Brown
IL-4 Induces the Proteolytic Processing of Mast Cell STAT6
J. Immunol., October 1, 2002; 169(7): 3811 - 3818.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
H. A. Foley, S. F. Ofori-Acquah, A. Yoshimura, S. Critz, B. S. Baliga, and B. S. Pace
Stat3beta Inhibits gamma -Globin Gene Expression in Erythroid Cells
J. Biol. Chem., May 3, 2002; 277(18): 16211 - 16219.
[Abstract] [Full Text] [PDF]


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JNCI J Natl Cancer InstHome page
V. Syed, G. Ulinski, S. C. Mok, and S.-M. Ho
Reproductive Hormone-Induced, STAT3-Mediated Interleukin 6 Action in Normal and Malignant Human Ovarian Surface Epithelial Cells
J Natl Cancer Inst, April 17, 2002; 94(8): 617 - 629.
[Abstract] [Full Text] [PDF]


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Mol. Endocrinol.Home page
S. Ray, C. T. Sherman, M. Lu, and A. R. Brasier
Angiotensinogen Gene Expression Is Dependent on Signal Transducer and Activator of Transcription 3-Mediated p300/cAMP Response Element Binding Protein-Binding Protein Coactivator Recruitment and Histone Acetyltransferase Activity
Mol. Endocrinol., April 1, 2002; 16(4): 824 - 836.
[Abstract] [Full Text] [PDF]


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Clin. Cancer Res.Home page
R. Buettner, L. B. Mora, and R. Jove
Activated STAT Signaling in Human Tumors Provides Novel Molecular Targets for Therapeutic Intervention
Clin. Cancer Res., April 1, 2002; 8(4): 945 - 954.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
C. Yan, A. Naltner, M. Martin, M. Naltner, J. M. Fangman, and O. Gurel
Transcriptional Stimulation of the Surfactant Protein B Gene by STAT3 in Respiratory Epithelial Cells
J. Biol. Chem., March 22, 2002; 277(13): 10967 - 10972.
[Abstract] [Full Text] [PDF]


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J. Leukoc. Biol.Home page
A. Lehtonen, S. Matikainen, M. Miettinen, and I. Julkunen
Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced STAT5 activation and target-gene expression during human monocyte/macrophage differentiation
J. Leukoc. Biol., March 1, 2002; 71(3): 511 - 519.
[Abstract] [Full Text] [PDF]


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BloodHome page
D. L. Hevehan, W. M. Miller, and E. T. Papoutsakis
Differential expression and phosphorylation of distinct STAT3 proteins during granulocytic differentiation
Blood, March 1, 2002; 99(5): 1627 - 1637.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
T. J. Ahonen, P. L. Harkonen, H. Rui, and M. T. Nevalainen
PRL Signal Transduction in the Epithelial Compartment of Rat Prostate Maintained as Long-Term Organ Cultures in Vitro
Endocrinology, January 1, 2002; 143(1): 228 - 238.
[Abstract] [Full Text] [PDF]


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BloodHome page
M. Benekli, Z. Xia, K. A. Donohue, L. A. Ford, L. A. Pixley, M. R. Baer, H. Baumann, and M. Wetzler
Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival
Blood, January 1, 2002; 99(1): 252 - 257.
[Abstract] [Full Text] [PDF]


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BloodHome page
H. Shao, A. J. Quintero, and D. J. Tweardy
Identification and characterization of cis elements in the STAT3 gene regulating STAT3alpha and STAT3beta messenger RNA splicing
Blood, December 15, 2001; 98(13): 3853 - 3856.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
C. M. Litterst and E. Pfitzner
Transcriptional Activation by STAT6 Requires the Direct Interaction with NCoA-1
J. Biol. Chem., November 30, 2001; 276(49): 45713 - 45721.
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Cancer Res.Home page
G. Niu, K. H. Shain, M. Huang, R. Ravi, A. Bedi, W. S. Dalton, R. Jove, and H. Yu
Overexpression of a Dominant-Negative Signal Transducer and Activator of Transcription 3 Variant in Tumor Cells Leads to Production of SolubleFactors That Induce Apoptosis and Cell Cycle Arrest
Cancer Res., April 1, 2001; 61(8): 3276 - 3280.
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J. Virol.Home page
H. Chen, J. M. Lee, Y. Zong, M. Borowitz, M. H. Ng, R. F. Ambinder, and S. D. Hayward
Linkage between STAT Regulation and Epstein-Barr Virus Gene Expression in Tumors
J. Virol., March 15, 2001; 75(6): 2929 - 2937.
[Abstract] [Full Text]


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Mol. Endocrinol.Home page
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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Cancer Res.Home page
Z. Xia, R. R. Salzler, D. P. Kunz, M. R. Baer, L. Kazim, H. Baumann, and M. Wetzler
A Novel Serine-dependent Proteolytic Activity Is Responsible for Truncated Signal Transducer and Activator of Transcription Proteins in Acute Myeloid Leukemia Blasts
Cancer Res., February 1, 2001; 61(4): 1747 - 1753.
[Abstract] [Full Text]


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EndocrinologyHome page
M.-L. Hakansson-Ovesjo, M. Collin, and B. Meister
Down-Regulated STAT3 Messenger Ribonucleic Acid and STAT3 Protein in the Hypothalamic Arcuate Nucleus of the Obese Leptin-Deficient (ob/ob) Mouse
Endocrinology, November 1, 2000; 141(11): 3946 - 3955.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
B. Emanuelli, P. Peraldi, C. Filloux, D. Sawka-Verhelle, D. Hilton, and E. Van Obberghen
SOCS-3 Is an Insulin-induced Negative Regulator of Insulin Signaling
J. Biol. Chem., May 19, 2000; 275(21): 15985 - 15991.
[Abstract] [Full Text] [PDF]


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Mol. Cell. Biol.Home page
Y.-T. Tsai, Y.-H. Su, S.-S. Fang, T.-N. Huang, Y. Qiu, Y.-S. Jou, H.-m. Shih, H.-J. Kung, and R.-H. Chen
Etk, a Btk Family Tyrosine Kinase, Mediates Cellular Transformation by Linking Src to STAT3 Activation
Mol. Cell. Biol., March 15, 2000; 20(6): 2043 - 2054.
[Abstract] [Full Text]


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BloodHome page
A. C. Ward, I. Touw, and A. Yoshimura
The Jak-Stat pathway in normal and perturbed hematopoiesis
Blood, January 1, 2000; 95(1): 19 - 29.
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Mol. Cell. Biol.Home page
J. Turkson, T. Bowman, J. Adnane, Y. Zhang, J. Y. Djeu, M. Sekharam, D. A. Frank, L. B. Holzman, J. Wu, S. Sebti, et al.
Requirement for Ras/Rac1-Mediated p38 and c-Jun N-Terminal Kinase Signaling in Stat3 Transcriptional Activity Induced by the Src Oncoprotein
Mol. Cell. Biol., November 1, 1999; 19(11): 7519 - 7528.
[Abstract] [Full Text] [PDF]


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Cancer Res.Home page
G. Niu, R. Heller, R. Catlett-Falcone, D. Coppola, M. Jaroszeski, W. Dalton, R. Jove, and H. Yu
Gene Therapy with Dominant-negative Stat3 Suppresses Growth of the Murine Melanoma B16 Tumor in Vivo
Cancer Res., October 1, 1999; 59(20): 5059 - 5063.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
A. Woetmann, M. Nielsen, S. T. Christensen, J. Brockdorff, K. Kaltoft, A.-M. Engel, S. Skov, C. Brender, C. Geisler, A. Svejgaard, et al.
Inhibition of protein phosphatase 2A induces serine/threonine phosphorylation, subcellular redistribution, and functional inhibition of STAT3
PNAS, September 14, 1999; 96(19): 10620 - 10625.
[Abstract] [Full Text] [PDF]


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BloodHome page
R. P. de Groot, J. A.M. Raaijmakers, J.-W. J. Lammers, R. Jove, and L. Koenderman
STAT5 Activation by BCR-Abl Contributes to Transformation of K562 Leukemia Cells
Blood, August 1, 1999; 94(3): 1108 - 1112.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
M. A. Sherman, V. H. Secor, and M. A. Brown
IL-4 Preferentially Activates a Novel STAT6 Isoform in Mast Cells
J. Immunol., March 1, 1999; 162(5): 2703 - 2708.
[Abstract] [Full Text] [PDF]


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Mol. Endocrinol.Home page
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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BloodHome page
A. Chakraborty, K. F. Dyer, M. Cascio, T. A. Mietzner, and D. J. Tweardy
Identification of a Novel Stat3 Recruitment and Activation Motif Within the Granulocyte Colony-Stimulating Factor Receptor
Blood, January 1, 1999; 93(1): 15 - 24.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Cell Physiol.Home page
A. R. Simon, U. Rai, B. L. Fanburg, and B. H. Cochran
Activation of the JAK-STAT pathway by reactive oxygen species
Am J Physiol Cell Physiol, December 1, 1998; 275(6): C1640 - C1652.
[Abstract] [Full Text] [PDF]


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BloodHome page
T. B. van Dijk, B. Baltus, E. Caldenhoven, H. Handa, J. A.M. Raaijmakers, J.-W. J. Lammers, L. Koenderman, and R. P. de Groot
Cloning and Characterization of the Human Interleukin-3 (IL-3)/IL-5/ Granulocyte-Macrophage Colony-Stimulating Factor Receptor beta c Gene: Regulation by Ets Family Members
Blood, November 15, 1998; 92(10): 3636 - 3646.
[Abstract] [Full Text] [PDF]


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Stem CellsHome page
E. Caldenhoven, T. B. van Dijk, A. Tijmensen, J. A.M. Raaijmakers, J.-W. J. Lammers, L. Koenderman, and R. P. de Groot
Differential Activation of Functionally Distinct STAT5 Proteins by IL-5 and GM-CSF During Eosinophil and Neutrophil Differentiation from Human CD34+ Hematopoietic Stem Cells
Stem Cells, November 1, 1998; 16(6): 397 - 403.
[Abstract] [Full Text]


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J. Immunol.Home page
R. Imamura, E. S. Masuda, Y. Naito, S.-i. Imai, T. Fujino, T. Takano, K.-i. Arai, and N. Arai
Carboxyl-Terminal 15-Amino Acid Sequence of NFATx1 Is Possibly Created by Tissue-Specific Splicing and Is Essential for Transactivation Activity in T Cells
J. Immunol., October 1, 1998; 161(7): 3455 - 3463.
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Mol. Endocrinol.Home page
M. Dajee, G. H. Fey, and J. S. Richards
Stat 5b and the Orphan Nuclear Receptors Regulate Expression of the {alpha}2-Macroglobulin ({alpha}2M) Gene in Rat Ovarian Granulosa Cells
Mol. Endocrinol., September 1, 1998; 12(9): 1393 - 1409.
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J. Immunol.Home page
T. Mikita, M. Kurama, and U. Schindler
Synergistic Activation of the Germline {epsilon} Promoter Mediated by Stat6 and C/EBP{beta}
J. Immunol., August 15, 1998; 161(4): 1822 - 1828.
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J. Biol. Chem.Home page
C. Bovolenta, L. Testolin, L. Benussi, P. M.-J. Lievens, and E. Liboi
Positive Selection of Apoptosis-resistant Cells Correlates with Activation of Dominant-Negative STAT5
J. Biol. Chem., August 14, 1998; 273(33): 20779 - 20784.
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J. Biol. Chem.Home page
T. Bellido, C. A. O'Brien, P. K. Roberson, and S. C. Manolagas
Transcriptional Activation of the p21WAF1,CIP1,SDI1 Gene by Interleukin-6 Type Cytokines. A PREREQUISITE FOR THEIR PRO-DIFFERENTIATING AND ANTI-APOPTOTIC EFFECTS ON HUMAN OSTEOBLASTIC CELLS
J. Biol. Chem., August 14, 1998; 273(33): 21137 - 21144.
[Abstract] [Full Text] [PDF]


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BloodHome page
S. Skov, M. Nielsen, S. Bregenholt, N. Odum, and M. H. Claesson
Activation of Stat-3 Is Involved in the Induction of Apoptosis After Ligation of Major Histocompatibility Complex Class I Molecules on Human Jurkat T Cells
Blood, May 15, 1998; 91(10): 3566 - 3573.
[Abstract] [Full Text] [PDF]


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Mol. Cell. Biol.Home page
J. Turkson, T. Bowman, R. Garcia, E. Caldenhoven, R. P. De Groot, and R. Jove
Stat3 Activation by Src Induces Specific Gene Regulation and Is Required for Cell Transformation
Mol. Cell. Biol., May 1, 1998; 18(5): 2545 - 2552.
[Abstract] [Full Text]


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BloodHome page
K. Inoue, H. Tamaki, H. Ogawa, Y. Oka, T. Soma, T. Tatekawa, Y. Oji, A. Tsuboi, E. H. Kim, M. Kawakami, et al.
Wilms' Tumor Gene (WT1) Competes With Differentiation-Inducing Signal in Hematopoietic Progenitor Cells
Blood, April 15, 1998; 91(8): 2969 - 2976.
[Abstract] [Full Text] [PDF]


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BloodHome page
T. B. van Dijk, E. Caldenhoven, J. A.M. Raaijmakers, J.-W. J. Lammers, L. Koenderman, and R. P. de Groot
The Role of Transcription Factor PU.I in the Activity of the Intronic Enhancer of the Eosinophil-Derived Neurotoxin (RNS2) Gene
Blood, March 15, 1998; 91(6): 2126 - 2132.
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Proc. Natl. Acad. Sci. USAHome page
B. K. R. Patel, J. H. Pierce, and W. J. LaRochelle
Regulation of interleukin 4-mediated signaling by naturally occurring dominant negative and attenuated forms of human Stat6
PNAS, January 6, 1998; 95(1): 172 - 177.
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Proc. Natl. Acad. Sci. USAHome page
S. Takemoto, J. C. Mulloy, A. Cereseto, T.-S. Migone, B. K. R. Patel, M. Matsuoka, K. Yamaguchi, K. Takatsuki, S. Kamihira, J. D. White, et al.
Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins
PNAS, December 9, 1997; 94(25): 13897 - 13902.
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M. J. Walter, D. C. Look, R. M. Tidwell, W. T. Roswit, and M. J. Holtzman
Targeted Inhibition of Interferon-gamma -dependent Intercellular Adhesion Molecule-1 (ICAM-1) Expression Using Dominant-Negative Stat1
J. Biol. Chem., November 7, 1997; 272(45): 28582 - 28589.
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J. Ng and D. Cantrell
STAT3 Is a Serine Kinase Target in T Lymphocytes. INTERLEUKIN 2 AND T CELL ANTIGEN RECEPTOR SIGNALS CONVERGE UPON SERINE 727
J. Biol. Chem., September 26, 1997; 272(39): 24542 - 24549.
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Proc. Natl. Acad. Sci. USAHome page
M. Nielsen, K. Kaltoft, M. Nordahl, C. Ropke, C. Geisler, T. Mustelin, P. Dobson, A. Svejgaard, and N. Odum
Constitutive activation of a slowly migrating isoform of Stat3 in mycosis fungoides: Tyrphostin AG490 inhibits Stat3 activation and growth of mycosis fungoides tumor cell lines
PNAS, June 24, 1997; 94(13): 6764 - 6769.
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K. K. Kuropatwinski, C. De Imus, D. Gearing, H. Baumann, and B. Mosley
Influence of Subunit Combinations on Signaling by Receptors for Oncostatin M, Leukemia Inhibitory Factor, and Interleukin-6
J. Biol. Chem., June 13, 1997; 272(24): 15135 - 15144.
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H. Kim and H. Baumann
The Carboxyl-terminal Region of STAT3 Controls Gene Induction by the Mouse Haptoglobin Promoter
J. Biol. Chem., June 6, 1997; 272(23): 14571 - 14579.
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J. Biol. Chem.Home page
R. A. Kirken, M. G. Malabarba, J. Xu, X. Liu, W. L. Farrar, L. Hennighausen, A. C. Larner, P. M. Grimley, and H. Rui
Prolactin Stimulates Serine/Tyrosine Phosphorylation and Formation of Heterocomplexes of Multiple Stat5 Isoforms in Nb2 Lymphocytes
J. Biol. Chem., May 30, 1997; 272(22): 14098 - 14103.
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J. Biol. Chem.Home page
R. P. de Groot, T. B. van Dijk, E. Caldenhoven, P. J. Coffer, J. A.M. Raaijmakers, J.-W. J. Lammers, and L. Koenderman
Activation of 12-O-Tetradecanoylphorbol-13-acetate Response Element- and Dyad Symmetry Element-dependent Transcription by Interleukin-5 Is Mediated by Jun N-terminal Kinase/Stress-activated Protein Kinase Kinases
J. Biol. Chem., January 24, 1997; 272(4): 2319 - 2325.
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Y. Zhang, J. Turkson, C. Carter-Su, T. Smithgall, A. Levitzki, A. Kraker, J. J. Krolewski, P. Medveczky, and R. Jove
Activation of Stat3 in v-Src-transformed Fibroblasts Requires Cooperation of Jak1 Kinase Activity
J. Biol. Chem., August 4, 2000; 275(32): 24935 - 24944.
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O. K. Park, L. K. Schaefer, W. Wang, and T. S. Schaefer
Dimer Stability as a Determinant of Differential DNA Binding Activity of Stat3 Isoforms
J. Biol. Chem., October 6, 2000; 275(41): 32244 - 32249.
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Proc. Natl. Acad. Sci. USAHome page
T. Bowman, M. A. Broome, D. Sinibaldi, W. Wharton, W. J. Pledger, J. M. Sedivy, R. Irby, T. Yeatman, S. A. Courtneidge, and R. Jove
Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis
PNAS, June 19, 2001; 98(13): 7319 - 7324.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
T. R. Faruqi, D. Gomez, X. R. Bustelo, D. Bar-Sagi, and N. C. Reich
Rac1 mediates STAT3 activation by autocrine IL-6
PNAS, July 31, 2001; 98(16): 9014 - 9019.
[Abstract] [Full Text] [PDF]


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