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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 3 (August 1), 1999:
pp. 1108-1112
STAT5 Activation by BCR-Abl Contributes to Transformation of K562
Leukemia Cells
By
Rolf P. de Groot,
Jan A.M. Raaijmakers,
Jan-Willem J. Lammers,
Richard Jove, and
Leo Koenderman
From the Department of Pulmonary Diseases, University Hospital
Utrecht, Utrecht, The Netherlands; and the Molecular Oncology Program,
H. Lee Moffit Cancer Center and Research Institute, University of South
Florida College of Medicine, Tampa, FL.
 |
ABSTRACT |
Signal transducers and activators of transcription (STATs) belong to
a family of transcription factors that were originally identified as
mediators of cytokine-induced gene expression. Recent evidence,
however, has shown that certain members of the STAT family, including
STAT3, are also involved in cellular transformation. Here we show that
STAT5 also plays a role in cellular transformation by the BCR-Abl
oncogene. In BCR-Abl transformed K562 cells, STAT5A and 5B are
constitutively phosphorylated on tyrosine and are transcriptionally active. Moreover, expression of a dominant negative form of STAT5 shows
that active STAT5 is necessary for the growth in soft agar of these
cells. These results show that besides STAT3, STAT5 can also be
involved in cellular transformation.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
JANUS KINASES (JAKs) are a family of
cytoplasmic tyrosine kinases, which are associated with cytokine and
growth factor receptors and play a major role in cytokine
signaling.1-3 On ligand binding, the JAKs are activated and
subsequently phosphorylate a number of substrates including cytokine
receptors. The phosphorylated receptors provide docking sites for the
SH-2 domain containing STAT transcription factor family (signal
transducers and activators of transcription). Subsequently, STATs are
phosphorylated on a single tyrosine residue by the JAKs, after which
the STATs dimerize, migrate into the nucleus, and regulate gene
transcription. Although the signaling pathway seems rather simple, the
availability of four different JAKs (JAK1, JAK2, JAK3, and Tyk2) and at
least eight different STATs (STAT1 , STAT1 , STAT2, STAT3,
STAT3, STAT4, STAT5A, STAT5B, and STAT6) all with different DNA
binding and transactivation properties allows cellular specificity in
this signaling pathway.1-3
Several studies have shown that STAT proteins are essential for
cytokine-regulated processes such as cellular proliferation, differentiation, as well as survival.4,5 However, more
recently, it has become evident that aberrant activation of STAT
proteins is often associated with cellular transformation by various
oncoproteins.6 Cells transformed by v-Abl or BCR-Abl
contain constitutively activated STAT1, STAT3, and
STAT5.7-14 Similarly, activation of STAT1, 3, and 5 was
observed in several cell lines transformed by v-Src,15-22 while the Eyk oncoprotein induces activation of STAT1 and
STAT3.23 More importantly, activation of STATs 1, 3, and 5 was reported in several human malignancies, including lymphomas,
leukemias, and breast carcinoma.19,24-29 Although these
observations strongly suggest that STAT1, 3, and 5 can play a role in
cellular transformation, an essential role for STAT activation was only
demonstrated in v-Src transformed cells. Dominant negative variants of
STAT3 clearly inhibited transformation of fibroblasts by
v-Src.18,22 Evidence for an obligatory role of STAT1 and
STAT5 in cellular transformation is currently lacking.
The BCR/ABL chimeric oncogene, a constitutively active tyrosine kinase,
which is generated from the Philadelphia chromosome translocation
(t(9;22)(q34;q11)), causes chronic myelogenous leukemia (CML).30 Although it is clear that the tyrosine kinase
activity of BCR/ABL is essential for transformation,31,32
the actual mechanism by which BCR/ABL transforms cells remains largely
unknown. Interestingly, BCR/ABL constitutively activates several
signaling pathways33 that are also used by several
cytokines, including those of the interleukin-5
(IL-5)/IL-3/granulocyte-macrophage colony-stimulating factor (GM-CSF)
cytokine family.34 These pathways include the RAS-Erk2, the
PI3Kinase, and the JAK/STAT pathways.33 In addition,
BCR/ABL activates the phosphatases SHP1 and SHP2, which also play a
pivotal role in IL-5/IL-3/GM-CSF signaling. Among the STATs, which are
found to be activated in various BCR/Abl-expressing cell lines, STAT5
seems to be the most prominent.7-14 Because STAT5 was shown
to be necessary for cellular proliferation induced by the
IL-5/IL-3/GM-CSF cytokine family35 and overexpression of
constitutively active STAT5 stimulates cell proliferation,36 it seems conceivable that it also might
contribute to cellular transformation by BCR/Abl.
In this report, we have investigated the contribution of STAT5 to
cellular transformation by the BCR/Abl oncogene. In K562 cells, we show
that STAT5 (A and B) is constitutively phosphorylated on tyrosine and
bind to a STAT5 binding site. Similarly, reporter constructs containing
STAT5 binding sites are active in these cells. Importantly, we show
that blocking STAT5 activity with a dominant negative expression vector
significantly decreases soft agar growth of K562 cells, as well as
transformation of fibroblasts by v-Src. These results suggest that
STAT5 plays an important role in cellular transformation.
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MATERIALS AND METHODS |
Cell culture.
U937 and K562 cells were maintained in RPMI 1640 supplemented with 8%
fetal calf serum (FCS) (Hyclone, Greiner, Logan, UT). NIH 3T3 cells
were grown in Dulbecco's modified Eagle's medium (DMEM)
containing 8% FCS (Life Technologies, Breda, The Netherlands). Focus
assays on NIH-3T3 cells were performed as described previously.
Reagents and antibodies.
The phosphotyrosine monoclonal antibody (MoAb) 4G10 was obtained from
UBI (Lake Placid, NY). The MoAb anti-STAT1 (S21120, directed against
amino acids [aa] 592-731) was obtained from Transduction laboratory
(Lexington, KY). The polyclonal antibodies (pAb) directed against STAT3
(C-20, aa 750-769), STAT5A (L-20, aa 774-793), STAT5B (C-17, aa
711-727), and STAT5 (N-20, aa 5-24) were obtained from Santa Cruz
Biotechnology (Santa Cruz, CA).
Synthetic oligonucleotides and plasmids.
The following oligonucleotide was used in this study (only the upper
strands are shown); for bandshift assays: -casein
(5'-AGCTTAGATTTCTAGGAATTCAA ATCA-3'). The expression
plasmids pMXmSTAT5A, pMXmSTAT5A,  75037 (a kind gift of
Dr Fabrice Gouilleux, Tumor Biology Center, Freiburg, Germany),
pSG5-STAT3, pSG5-STAT3, and pMvSrc were described
previously.22,38 Full-length cDNAs of the different STATs
were excised from the plasmids described above and cloned into the LNCX
expression vector (Clontech, Palo Alto, CA), which contains a neomycin
resistance gene. The reporter constructs 4xIREtkCAT, 4xGAStkCAT,
4xSIEtkCAT, and 4xCaseintkCAT were previously
described.38,39
Transfection of K562 cells.
For transient assays, K562 cells were electroporated with 2 µg of
reporter plasmid and 10 µg of bluescript SK carrier DNA. For
some experiments, dominant negative expression vectors for STAT3 or
STAT5 were cotransfected instead of bluescript SK. Cells were
harvested for CAT assays 48 hours after transfection.
Chloramphenicol acetyltransferase (CAT) assays were performed as
described previously.38
For soft agar assays, 24 hours posttransfection K562 cells were treated
with 1 mg/mL G418 for 10 days. Cells were then plated in soft agar and
scored as was described previously,40 except that RPMI 1640 with 10% FCS was used as medium.
Gel retardation assay.
Nuclear extracts were prepared following a previously described
procedure.41 Oligonucleotides were labeled by filling in the cohesive ends with [a-32P]deoxycytidine triphosphate
(dCTP) using Klenow fragment of DNA polymerase I. Gel
retardation assays were performed according to published
procedures.38 Supershift analysis was performed by
preincubating 10 µg of nuclear extract with 1 µg of anti-STAT antibody for 30 minutes on ice before addition of the binding buffer
and 32P-labeled probe.
Immunoprecipitation/Western blotting.
K562 cells (10.106 per sample) were washed with ice-cold
phosphate-buffered saline and subsequently lysed in 750 µL
radioimmunoprecipitation assay (RIPA) buffer (150 mmol/L NaCl, 20 mmol/L Tris pH 7.4, 5 mmol/L EDTA, 1% Nonidet P-40, 0.1% sodium
dodecyl sulfate [SDS], 0.5% sodium deoxycholate, 1 mmol/L
phenylmethylsulphonylfluoride [PMSF], 2 µg/mL leupeptin, 4 µg/mL
aprotinin, 1.5 µg/mL pepstatin, 1 µg/mL trypsin inhibitor, and 50 mmol/L NaF) for 10 minutes on ice. Cell lysates were centrifuged to
remove the insoluble material, and supernatants were precleared with
protein A-Sepharose beads for 15 minutes at 4°C. Thereafter,
supernatants were incubated with STAT antibodies for 1.5 hours at
4°C. Protein A-Sepharose was added to the reaction mixture and the
incubation was continued for 45 minutes. Beads were collected by
centrifugation and washed eight times with cold RIPA buffer,
resuspended in Laemmli sample buffer, and boiled for 3 minutes. Protein
samples were separated on 8% SDS-polyacrylamide gels, and
electrotransferred to Immobilon-P membranes (Millipore, Bedford MA).
Membranes were blocked in TBST-buffer (150 mmol/L NaCl, 10 mmol/L Tris
pH 8.0, 0.3% Tween 20) containing 5% bovine serum albumin (BSA) for
30 minutes and probed with either an antiphosphotyrosine MoAb 4G10 or
the anti-STAT antibodies described above for 1 hour. After three washes
with TBST, the membranes were incubated for 1 hour with either
peroxidase-conjugated rabbit antimouse antibodies (after MoAb) or
peroxidase-conjugated swine antirabbit antibodies (DAKO,
Glostrup, Denmark) (after pAb), followed by five washes
with TBST. Proteins were visualized with enhanced chemiluminescence
(ECL; Amersham, Buckinghamshire, UK).
| |
RESULTS AND DISCUSSION |
Previously, it was demonstrated that BCR/Abl activates STAT5, although
activation of STAT1 was also reported in some cell types.7-14 To determine which STAT family members were
activated in BCR/Abl-expressing K562 cells, we performed
immunoprecipitation/Western blotting experiments using antiserum
specific for STAT1, 3, 5A, and 5B. Figure
1A shows that both STAT5A and 5B are phosphorylated on tyrosine
residues in these cells. The second band observed in the STAT5B
immunoprecipitation is likely to be caused by serine phosphorylation of
STAT5B (data not shown). By contrast, activation of STAT1 or 3 could
not be detected. These results were confirmed by gel-shift analysis.
Figure 1B shows that STAT5A and 5B constitutively bind to the STAT
binding site from the -casein promoter and from the Fc RI promoter
(not shown), while DNA binding of STAT1 and STAT3 could not be
observed. These results clearly show that STAT5A and 5B are the major
targets for BCR/Abl in K562 cells.
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| Fig 1.
Constitutive activation of STAT5A and 5B in K562 cells.
(A) K562 cells (3.106 per lane) and U937 cells (negative
control) were lysed in RIPA buffer, after which the tyrosine
phosphorylation state of different STAT molecules was assessed by
immunoprecipitation and Western blotting. Probing the blot with an
antiphosphotyrosine antibody clearly shows that only STAT5A and STAT5B
are phosphorylated on tyrosine in K562 cells. (B) Nuclear extracts from
K562 cells were analyzed in a gel shift assay using the STAT binding
site from the -casein promoter as a probe. Supershift analysis
clearly shows that STAT5A and 5B constitutively bind to the -casein
site in K562 cells.
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Although tyrosine phosphorylation and DNA binding of STAT5 was
previously reported in BCR/Abl-expressing cells, transcriptional activation of STAT5-dependent promoters was not shown. We therefore transfected various STAT-dependent reporter constructs into K562 cells.
Figure 2A shows that constructs containing
STAT binding sites from the -casein promoter (which can bind STAT1
and STAT5) and from the FcRI promoter (GAS, which can bind STATs 1, 3, and 5) are more active than the TK-CAT control reporter. By
contrast, the IRE-CAT and SIE-CAT reporters, which cannot bind STAT5,
are comparable to the TK-CAT control reporter. These results suggest that STAT5 is indeed transcriptionally active in K562 cells. To further
extend these results, we transfected K562 cells with the -casein-CAT
reporter together with either dominant-negative STAT5 (STAT5 750) or
STAT3 (Fig 2B). While STAT3 did not significantly alter the
activity of the -casein-CAT reporter, STAT5750 caused a strong
repression of CAT activity, further suggesting that STAT5 is
transcriptionally active in these cells.
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| Fig 2.
STAT5 is transcriptionally active in K562 cells. (A) K562
cells were transfected with different reporter plasmids (2 µg) by
electroporation. Two days posttransfection, cells were harvested and
CAT activity was determined. The two reporters containing STAT5 binding
sites (-casein-CAT and GAS-CAT) were more active compared with the
empty reporter and the reporters containing STAT1 and STAT3 binding
sites (IRE-CAT and SIE-CAT). (B) K562 cells were transfected with as
described in (A) with 2 µg -casein CAT and increasing amounts of
dominant negative (DN) STAT5 (750) or STAT3 (STAT3). Only DN
STAT5 is able to (partially) block the activity of the -casein-CAT
reporter in K562 cells.
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In contrast with most nontransformed hematopoietic cells, one of the
transformed properties of K562 cells is their ability to grow in
semisolid media (soft agar). To determine whether activation of STAT5
is involved in this property of K562 cells, we used STAT5750. K562
cells were transfected with STAT5750, STAT3, or the empty expression vector (LNCX), after which the transfected cells were selected in G418-containing media for 10 days. Thereafter, cells were
plated in dishes containing soft agar. Figure 3 shows
that K562 cells transfected with an empty expression vector (LNCX) grow
efficiently in soft agar (Fig 3A and D). By contrast, K562 cells
transfected with STAT5750 form fewer and smaller colonies in soft
agar (Fig 3B and D), suggesting that STAT5 is indeed involved in this
aspect of cellular transformation by BCR/Abl. As a control, cells
transfected with STAT3 grew as efficiently in soft agar as vector
controls, further showing that STAT3 is not involved in transformation
by BCR/Abl (Fig 3C and D).
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| Fig 3.
STAT5 is involved in soft agar growth of K562 cells. K562
cells were electroporated with STAT5750 (B and C), the empty
expression vector (LNCX, A and D), or STAT3 (C and D), after which
the cells were selected on G418 (1 mg/mL) for 10 days. Cells were then
plated in soft agar. Seven to 10 days later, colonies were counted as
described in Materials and Methods. STAT5750 partially inhibits the
capacity of K562 cells to grow in soft agar, while STAT3 did not
have an effect.
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We next wanted to investigate whether STAT5 also contributes to
transformation by other oncogenes. Recently, we and others have shown
that STAT3 is involved in cellular transformation by v-Src.18,22 Figure
4A shows that besides STAT3, STAT5A and 5B are also
tyrosine-phosphorylated in v-Src-transformed NIH-3T3 cells, but not in
the parental NIH-3T3 cells. However, in contrast to K562 cells, we
failed to detect substantial STAT5 DNA binding activity in
v-Src-transformed cells (data not shown). To investigate whether STAT5
is causally involved in v-Src-induced transformation, we performed
focus assays in NIH-3T3 cells. Transfection of NIH-3T3 cells with v-Src
efficiently induces focus formation in these cells (Fig 4B). As we have
previously shown, this can be strongly repressed by cotransfecting
STAT3. Interestingly, cotransfection of STAT5750 also represses
v-Src-dependent focus formation in NIH-3T3 cells, albeit much less
efficiently than STAT3. The combination of STAT3 and STAT5750
was somewhat more potent in repression focus formation than either
plasmid alone. In addition, the repression observed with STAT5750
could be overcome by cotransfection of wild-type STAT5, further
suggesting that STAT5 indeed plays a role in transformation by v-Src.
To rule out potential a-specific effects of STAT5750 on
STAT3-dependent signaling, we performed cotransfection of a
STAT3-dependent reporter construct (SIE-CAT) together with v-Src,
STAT3, and STAT5750. Figure 4C shows that STAT3 efficiently
blocks v-Src-induced SIE-CAT activity. By contrast, STAT5750 only
slightly reduced v-Src-induced SIE-CAT activity, suggesting that
STAT5750 does not repress STAT3 function in these cells. These
results show that although STAT3 is the major STAT involved in
transformation by the v-Src oncogene, STAT5 is also likely to play a
minor role.
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| Fig 4.
STAT5 is also involved in transformation by the v-Src
oncogene. (A) The tyrosine phosphorylation status of STAT3 and STAT5
was analyzed in NIH 3T3 cells and two derivatives that were transformed
by the v-Src oncogene. STAT3 and STAT5 are both constitutively
phosphorylated on tyrosine in v-Src-transformed, but not parental
NIH-3T3 cells. (B) NIH 3T3 cells were transfected with v-Src expression
plasmid and increasing concentrations of DN-STAT3 and DN-STAT5
expression vectors or wild-type STAT5 as a control. Two weeks after
transfection, foci were scored and represented as percent compared with
v-Src alone. Both DN STAT3 and DN STAT5 partially block transformation
of NIH 3T3 by v-Src, although DN STAT3 is much more potent. Wild-type
STAT5 could overcome the effect of STAT5750, but not STAT3. (C)
NIH-3T3 cells were transfected with the STAT3-dependent SIE-CAT
reporter plasmid and increasing amounts of STAT3 or STAT5750.
Only STAT3 is able to block v-Src-induced SIE-CAT activity.
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Taken together, we have shown that besides STAT3, STAT5 is also
involved in transformation mediated by at least two oncoproteins. The
mechanism by which active STAT5 contributes to cellular transformation remains to be determined, but is likely to involve constitutive activation of STAT5 target genes, which are somehow involved in the
control of proliferation (eg, c-fos). In this respect, it is noteworthy
that blocking STAT5 function in mouse BaF3 cells results in a
significant decrease in IL-3-dependent proliferation,35 while a constitutively active form of STAT5 renders IL-3-dependent cells partially IL-3-independent.36 On the other hand,
because STAT5 is involved in the regulation of the antiapoptotic Bcl2 homologue A1,42 enhanced survival and escape from apoptosis of cells containing active STAT5 might also contribute to cellular transformation. The availability of constitutively active STAT5 variants36,43 will undoubtedly give new insights into the
mechanism by which STAT5 contributes to cellular transformation.
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FOOTNOTES |
Submitted October 29, 1998; accepted April 8, 1999.
Supported by a research grant from GlaxoWellcome b.v.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Rolf P. de Groot, PhD,
Department of Pulmonary Diseases, Room G03.550, University Hospital
Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; e-mail:
R.deGroot{at}hli.azu.nl.
| |
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ABSTRACT
INTRODUCTION