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Journal of Virology, March 2001, p. 2161-2173, Vol. 75, No. 5
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.5.2161-2173.2001
CREB/ATF-Dependent Repression of Cyclin A by
Human T-Cell Leukemia Virus Type 1 Tax Protein
Karen V.
Kibler and
Kuan-Teh
Jeang*
Laboratory of Molecular Microbiology,
National Institute of Allergy and Infectious Diseases, Bethesda,
Maryland 20892-0460
Received 26 July 2000/Accepted 6 December 2000
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ABSTRACT |
Expression of the human T-cell leukemia virus type 1 (HTLV-1)
oncoprotein Tax is correlated with cellular transformation contributing to the development of adult T-cell leukemia. Tax has been shown to
modulate the activities of several cellular promoters. Existing evidence suggests that Tax need not directly bind to DNA to accomplish these effects but rather that it can act through binding to cellular factors, including members of the CREB/ATF family. Exact mechanisms of
HTLV-1 transformation of cells have yet to be fully defined, but the
process is likely to include both activation of
cellular-growth-promoting factors and repression of cellular
tumor-suppressing functions. While transcriptional activation has been
well studied, transcriptional repression by Tax, reported recently from
several studies, remains less well understood. Here, we show that Tax
represses the TATA-less cyclin A promoter. Repression of the cyclin A
promoter was seen in both ts13 adherent cells and Jurkat T lymphocytes.
Two other TATA-less promoters, cyclin D3 and DNA polymerase 
, were
also found to be repressed by Tax. Interestingly, all three promoters share a common feature of at least one conserved upstream CREB/ATF binding site. In electrophoretic mobility shift assays, we observed that Tax altered the formation of a complex(es) at the cyclin A
promoter-derived ATF site. Functionally, we correlated removal of the
CREB/ATF site from the promoter with loss of repression by Tax.
Furthermore, since a Tax mutant protein which binds CREB repressed the
cyclin A promoter while another mutant protein which does not bind CREB
did not, we propose that this Tax repression occurs through
protein-protein contact with CREB/ATF.
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INTRODUCTION |
Infection with human T-cell leukemia
virus type 1 (HTLV-1) has been linked to the development of several
diseases: adult T-cell leukemia (ATL), tropical spastic paraparesis,
and various neurological disorders termed HTLV-1-associated myelopathy
(33). The HTLV-1-encoded oncoprotein Tax has been
implicated in the transformation of T cells (reviewed in reference
91), as well as in tumor formation in transgenic mice
(26). Although the precise mechanisms utilized by Tax to
induce transformation are not known, this protein has been shown to
modulate cellular genes that are involved in cellular proliferation and
cell cycle control (reviewed in reference 55). Tax
up-regulates expression of interleukin-2 (IL-2), IL-2 receptor, c-fos,
c-Jun, erg-1, and granulocyte-macrophage colony-stimulating factor
(reviewed in references 32 and 51; 52) and
represses expression of the 
-polymerase, c-myb, Lck, and p53
promoters (11, 39, 48, 57, 84). Tax has also been shown to
affect the functions of IKK
(10, 27, 40), c-myc
(69), Bax (8), MAD1 (41), cyclin
D (56), and MyoD (63).
Cyclins are critical factors in cell cycle progression (25, 71,
72). Cyclins associate with cyclin-dependent kinases and
regulate the functions of cellular proteins that are required for
progression through the cell cycle (G1, S, G2,
and M) phases. The D cyclins are induced by growth factors and mediate
progression through G1. Cyclin A begins to accumulate after
the G1/S transition, and its associated kinase activity is
required for both completion of S phase and entry into as well as exit
from M phase (reviewed in reference 42). Aspects of cell
cycle progression have been well studied in a model system utilizing a
baby hamster kidney cell line, ts13, which is temperature sensitive for
the G1-to-S transition (82). ts13 exhibits a
growth defect at the restrictive temperature (39°C), which results
from a point mutation in cell cycle gene 1 (CCG1) (68).
CCG1 was subsequently shown to be identical to the gene for the
TAFII250 subunit of TFIID (31). At 39°C, a
subset of cell cycle-related promoters, including the cyclin A
(88), cyclin D3 (81), and DNA polymerase (44) promoters, is transcriptionally repressed. This
restricted-growth phenotype of ts13 at 39°C can be complemented by
overexpression of wild-type TAFII250 (88) and
the G1-specific cyclin D1 (67). Interestingly,
several viruses also encode functions that rescue the
G1-restricted phenotype of ts13. Thus, simian virus 40 (SV40) large T antigen (13) and hepatitis B virus (HBV) X
oncoprotein (29) also complement the CCG1 mutation in ts13 cells.
The findings for ts13 cells suggest that many viruses might encode a
CCG1/TAFII250-like activity. In principle, this makes sense
since viruses should evolve the ability to usurp the cell cycle
machinery for viral replicative benefits. How the HTLV retroviruses might behave in this regard has not been extensively investigated. Because Tax's properties as a transcriptional activator and as a
transforming protein resemble those of both SV40 T antigen (TAg) and
HBV X protein, we reasoned that Tax might have an X- or TAg-like CCG1/TAFII250 activity. Hence, using ts13 cells, we
investigated this possibility. Unexpectedly, we found that Tax, in
contrast to SV40 TAg or HBV X, failed to rescue the growth defect of
ts13 cells at the restrictive temperature. In attempting to define the
differences between Tax and TAg, we compared the transcriptional functions of the two on TAFII250-dependent promoters. We
observed that, whereas TAg activated TAFII250-dependent
expression of cyclin A in ts13 cells, Tax actually repressed the cyclin
A promoter.
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MATERIALS AND METHODS |
Cell lines.
ts13 cells are temperature sensitive baby
hamster kidney cells (82), which were cultured at 32°C.
ts13 cells and HeLa cells were propagated in Dulbecco's modified Eagle
medium (DMEM) supplemented with 10% fetal bovine serum (FBS; HyClone).
JPX9, a derivative of Jurkat cells, contains an inducible Tax cDNA
under the control of the metallothionein promoter (58).
Tax expression can be induced with zinc (120 µM ZnCl2) or
cadmium (20 µM CdCl2). TL-Su and ILT-Hod (from Mari
Kannagi, Tokyo Medical and Dental University, Tokyo, Japan) cells were
derived from peripheral blood lymphocytes of an HTLV-1 carrier and an
ATL patient, respectively. MT4 and C8166-45 are human T-cell lines
transformed by coculture with HTLV-1 producer cells. JPX9, Jurkat,
C8166-45, MT4, ILT-Hod, and TL-Su cells were cultured in RPMI 1640 supplemented with 10% FBS. ILT-Hod was maintained in RPMI 1640 supplemented with 10% FBS and 20 U of IL-2 (Boehringer Mannheim) per ml.
Plasmids.
pHpX (54), pU3RCAT
(7), and TaxH52Q (70) have been described
previously. LTR-luc was constructed by excising the HTLV-1 long
terminal repeat (LTR) from pU3RCAT at the XhoI
and HindIII restriction sites and reinserting the LTR
into pGL3-Pr (Promega) at the XhoI and
HindIII restriction sites. DPA
ATF was constructed by
synthesis of an oligomer consisting of the fragment from 
65 to +7 of
the DNA polymerase promoter (60) with XhoI
and HindIII restriction sites at the 5' and 3' ends,
respectively. The oligomer was then inserted into the XhoI
and HindIII sites of the pGL3-PR luciferase reporter
plasmid (Promega). pNFkB-luc was purchased from Stratagene. All other
plasmids were generous gifts of R. Tjian, Howard Hughes Medical
Institute, Berkeley, Calif. (CycA-luc and pCMVhTAFII250);
C. Z. Giam, U.S. Uniformed Health Services, Bethesda, Md. (TaxL90A
and TaxV89A); P. Hinds, Harvard Medical School, Boston, Mass.
(pCycD3-luc); T. Wang, Stanford University School of Medicine,
Stanford, Calif. (pDPA L5'); and K. Peden, Food and Drug
Administration, Bethesda, Md. (pRSVTAg).
Transfections.
Jurkat cells were transfected using SuperFect
(Qiagen) according to manufacturer's protocol. Briefly, 5.0 × 106 cells per well (six-well plate) were transfected with 3 to 10 µg of DNA and 20 µl of SuperFect reagent. The transfection
mixture was removed from cells after 4 h and replaced with
complete RPMI 1640 supplemented with 10% FBS. Cells were harvested 46 to 48 h after medium replacement. ts13 cells were transfected
using Lipofectamine (Life Technologies) according to the
manufacturer's protocol. Six-well plates were seeded at 50 to 60%
confluence and transfected the following day with 3 to 10 µg of DNA
and 12 µl of Lipofectamine reagent. The transfection mixture was
removed from cells after 4 h and replaced with complete DMEM
supplemented with 10% FBS. Plates were incubated at 32°C for 12 h, followed by incubation at 39°C for 24 h, and then harvested.
In all transfections, the total amount of DNA was equalized with pUC19.
Jurkat cell transfections were normalized to -galactosidase activity
expressed from a cotransfected cytomegalovirus -galactosidase
(Invitrogen) plasmid.
Luciferase assays.
Transfected cells were harvested after
two washes with PBS. Adherent cells were scraped into 250 µl, and
suspension cells were resuspended into 200 µl of reporter lysis
buffer (Promega). Lysates were prepared according to the protocol of
the manufacturer (Promega). Luciferase activity was measured in an
Optocomp II luminometer (MGM Instruments).
Electrophoretic mobility shift assay (EMSA).
A 21-bp
oligomer containing the terminal deoxynucleotidyltransferase (TdT)
initiator sequence or a 28- or 61-bp oligomer containing the
ATF-responsive element alone or the ATF element plus an initiator site
(Inr) were labeled with [-32P]ATP (Amersham Pharmacia)
using T4 polynucleotide kinase (New England Biolabs). Probes were added
(~30,000 cpm) to reaction mixtures (25 µl) containing 50 mM
Tris-HCl (pH 7.4), 10 mM MgCl2, 40 mM KCl, 20% glycerol,
0.5% Triton X-100, 5 mM EDTA, 5 mM dithiothreitol, 13.2 µg of salmon
sperm DNA per ml, and 2 µg of nuclear extract. JPX9 and Jurkat
nuclear extracts were prepared as described previously (17). MT4 and C8166-45 nuclear extracts were purchased
from Geneka Biotechnology, Inc. Reaction mixtures were incubated at room temperature for 30 min. Complexes were resolved in a 4%
polyacrylamide gel in 0.5 × Tris-borate-EDTA buffer at 180 V for
2 h and visualized by autoradiography.
Western blotting.
Approximately 107 cells were
harvested, washed twice in phosphate-buffered saline (PBS), and
resuspended into 200 µl of 2× sample buffer (100 mM Tris [pH 6.8],
4% sodium dodecyl sulfate, 20% glycerol, 5% -mercaptoethanol, and
0.05% bromphenol blue). Ten microliters was loaded onto a sodium
dodecyl sulfate-10% polyacrylamide gel and electrophoresed.
Afterwards, the gel was electroblotted onto Immobilon-P membranes
(Millipore Corp.) using a Millipore semidry blotting apparatus.
Visualization of antigens on the membrane was with rabbit antiserum
raised against Tax and used at a 1:1,000 dilution (38),
mouse monoclonal anti-cyclin A antibody used at a 1:500 dilution
(Upstate Biotechnology), or mouse monoclonal anti--actin antibody
used at a 1:20,000 dilution (Sigma). Incubation with primary antibody
was followed by incubation with goat anti-rabbit or goat anti-mouse
alkaline phosphatase-conjugated secondary antibody. Secondary
antibodies were used at a 1:10,000 dilution. Detection of secondary
antibody was by chemiluminescence (Tropix). Blots of JPX9 cells and
Jurkat cells (see Fig. 7) were probed for cyclin A and -actin
simultaneously. The JPX9 blot was then blocked and reprobed for Tax.
The blot shown in Fig. 8 was probed for cyclin A and -actin simultaneously.
Cell cycle synchronization.
Cells were cultured in the
presence of 2 mM thymidine (Sigma) in DMEM plus 10% FBS for 24 h,
allowed to recover in complete medium with no thymidine for 12 h,
and then propogated again in 2 mM thymidine for an additional 14 h.
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RESULTS |
Tax represses the cyclin A promoter in ts13 and Jurkat cells.
Because expression and replication of viruses frequently show cell
phase dependence, it is reasonable that some viruses would evolve to
control the cell cycle machinery of infected cells. HTLV-1 Tax, SV40
TAg, and HBV X are all transcriptional activators as well as
transforming proteins. Thus, initially, we wondered whether Tax would
conserve the CCG1/TAFII250-complementing activity shared by
SV40 TAg (13) and HBV X (29). To address
this, we checked for functions in ts13 cells. While we could
recapitulate the described activity of SV40 TAg in supporting the
growth of ts13 cells at the restrictive temperature (39°C), we found
that Tax provided no such function (K. V. Kibler, unpublished data).
TAg has also been shown to support temperature-sensitive
TAFII250-dependent transcription (13). Thus,
to understand better the divergence between Tax and TAg in ts13 cells,
we next surveyed the TAFII250-dependent transcription of
the well-characterized cyclin A promoter. We assayed for Tax effects on
a cyclin A promoter-luciferase reporter (CycA-luc [88])
by transfecting ts13 cells with CycA-luc alone, CycA-luc with a Tax
expression plasmid (pHpX), CycA-luc with a TAFII250
expression plasmid (pCMV-hTAFII250 [88]), or CycA-luc with a TAg expression plasmid (pRSV-TAg) (Fig.
1A). Compared to expression with CycA-luc
alone (activity set as 100%) (Fig. 1A, lane 1), coexpression of either
TAFII250 (Fig. 1A, lane 3) or SV40 TAg (Fig. 1A, lane 4)
increased luciferase expression by 50 and 180%, respectively. By
contrast, in the same assay, Tax repressed CycA-luc activity by 76%
(Fig. 1A, lane 2), with a dose-dependent profile (Fig. 1B). To rule out
nonspecific cytotoxicity as a trivial explanation for Tax's repression
of the cyclin A promoter, we also transfected ts13 cells with an HTLV-1
LTR chloramphenicol acetyltransferase reporter (pU3RCAT).
Figure 1C demonstrates that Tax activated pU3RCAT as it
repressed CycA-luc, rendering it unlikely that observations of the
latter occur from nonspecific cytotoxicity.
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FIG. 1.
Tax represses the cyclin A promoter. (A) The cyclin A
promoter is activated in ts13 cells at 39°C by either human
TAFII250 or SV40 TAg but is repressed by Tax. Cells were
transfected with CycA-luc alone (1 µg) (lane 1), CycA-luc plus pHpX
(Tax expression vector, 2 µg) (lane 2), CycA-luc plus
pCMV-hTAFII250 (2 µg) (lane 3), or CycA-luc plus pRSV-TAg
(2 µg) (lane 4). Transfected cells were incubated at the permissive
temperature (32°C) for 12 h and then at the restrictive
temperature (39°C) for 24 h and harvested. Results are averages
from five independent experiments. Error bars show standard deviations
of the means. (B) ts13 cells were transfected as described above with
either CycA-luc alone (1 µg) (lane 1) or increasing amounts (as
indicated) of pHpX (lanes 2 to 4). Results are averages from five
independent experiments. (C) Tax activates the HTLV-1 LTR
(pU3RCAT) in ts13 cells at 39°C. ts13 cells were
transfected with pU3RCAT (1 µg), with (lane 2) or without
(lane 1) Tax (2 µg). Chloramphenicol acetyltransferase (CAT) assays
were performed as described previously (24).
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To verify that the effect of Tax on CycA-luc was not idiosyncratic to
ts13 cells, we also tested Jurkat T cells. Because several
other
TATA-less promoters also show TAF
II250-dependent
expression,
we assayed two additional promoters, DNA polymerase
and
cyclin
D3, in combination with the luciferase reporter (DPA-luc plasmid
[
60] and CycD3-luc plasmid [gift of P. Hind],
respectively);
both of these promoters, like cyclin A, conserve a
promoter-upstream
CREB/ATF binding site (Fig.
2A). When these three
promoter-reporter
plasmids were separately assayed in Jurkat cells, we
observed
that Tax efficiently repressed transcription from CycA-luc
(Fig.
2B, lane 2), DPA-luc (Fig.
2B, lane
6), and CycD3-luc (Fig.
2B,
lane 10) to 28, 19, and 12% of baseline
activities, respectively.
When CREB was exogenously overexpressed
by transfection, we found
that Tax repression of CycA-luc was
ameliorated (data not shown).
These results taken together with the
above findings (Fig.
1)
indicate that Tax, in both ts13 and Jurkat
backgrounds, exerts
a consistently repressive effect on several
CREB/ATF-binding-site-containing
TATA-less promoters.
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FIG. 2.
Tax represses cyclinA, cyclin D3, and DNA polymerese promoters in Jurkat T cells. (A) Schematic representations of the
cyclin A (30), the cyclin D3 (9), and the DNA
polymerase (60) promoters showing approximate
positions of transcription factor binding elements and the
transcription start sites (Inr[INR]). SRE, serum response element.
(B) Tax represses the expression of these promoters in Jurkat cells.
Jurkat cells were transfected with either the promoter-reporter alone
(1 µg) (lane 1), the reporter plus 2 µg of Tax (lane 2), the
reporter plus 2 µg of TAFII250 (lane 3), or the reporter
plus 2 µg of TAg (lane 4). Results are averages from two independent
experiments.
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Tax abrogates activation by TAFII250 or TAg.
How
might Tax mechanistically repress the cyclin A, DNA polymerase , or
cyclin D3 promoter? Both TAFII250 and TAg complement the
transcription of the cyclin A, DNA polymerase , or cyclin D3
promoter at the restrictive temperature in ts13 cells (Fig. 1A and data
not shown). To understand if the repressive effect of Tax directly
negates the activating effects of TAFII250 and/or TAg, we
checked cotransfections of Tax with TAFII250 or SV40 TAg. Figure 3 shows results of Tax with
CycA-luc plus TAFII250 (Fig. 3A), Tax with CycA-luc plus
TAg (Fig. 3B), Tax with DPA-luc plus TAFII250 (Fig. 3C),
and Tax with DPA-luc plus TAg (Fig. 3D). In these experiments, we noted
that TAFII250 enhanced expression of CycA-luc and DPA-luc
to 141% (Fig. 3A, lane 2) and 323% (Fig 3C, lane 2), respectively.
However, with increasing amounts of cotransfected Tax, the activating
effects of TAFII250 were abrogated (Fig. 3A and C, lanes 3 to 5). Similar findings also documented Tax's abrogation of the
activation by TAg of either CycA-luc (Fig. 3B) or DPA-luc (Fig. 3D).
Collectively, these results show that Tax repression at the assayed
promoters is dominant over activation by either TAFII250 or
SV40 TAg.
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FIG. 3.
Activities of TAFII250 and TAg are repressed
by Tax in ts13 cells. ts13 cells were transfected with 1 µg of
CycA-luc (A and B) or DPA-luc (C and D). (A) CycA-luc was cotransfected
with TAFII250 (2 µg) and increasing amounts of Tax. (B)
CycA-luc was cotranfected with TAg (2 µg) and increasing amounts of
Tax. (C and D) Transfections of DPA-luc with either
TAFII250 (C) or TAg (D) and increasing amounts of Tax.
Results are averages from a minimum of five independent experiments.
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Repression by Tax correlates with the CREB/ATF binding site.
In ts13 cells, it has been proposed that disruption of the
TAFII250 interaction with factors bound to a
promoter-upstream CREB/ATF site upstream of the promoter
(89) explains the CycA expression defect at the
restrictive temperature. Because Tax additively repressed expression
from the cyclin A promoter in ts13 cells at 39°C, and because Tax is
known to bind CREB/ATF directly (22, 77, 83), we reasoned
that physical sequestration by Tax might explain transcriptional
repression. To correlate repression with Tax and CREB/ATF interaction,
we transfected ts13 cells with a Tax H52Q point mutation protein
(TaxH52Q) (22) which is defective in binding to CREB.
Interestingly, while wild-type Tax repressed both basal (Fig.
4A, lane 2) and
TAFII250-activated (Fig. 4A, lane 5) expression of
CycA-luc, TaxH52Q failed to do either (Fig. 4A, lanes 3 and 6). TaxH52Q
is deficient for activation of the HTLV-1 LTR but retains the ability
to activate promoters through NF-
B binding sites (70).
To verify that the lack of repression of the cyclin A promoter by
TaxH52Q did not result trivially from reduced protein expression, we
compared levels of induction of an NF-B-responsive reporter
(pNFB-luc) by Tax and TaxH52Q (Fig. 4B, lanes 5 and 6). Consistent
with there being comparable levels of protein expression, TaxH52Q
activated pNFB-luc to a magnitude similar to that activated by
wild-type Tax while it did not activate the HTLV-1 LTR-responsive
reporter (LTR-luc) (Fig. 4B, lane 3). Similarly, repression of DPA-luc
was also found to correlate with Tax proteins competent for binding
CREB/ATF (data not shown). These results are consistent with Tax
repression requiring physical Tax-CREB contact.
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FIG. 4.
Repression of the cyclin A and DNA polymerase promoters by Tax involves interaction with CREB/ATF. (A) ts13 cells
were transfected with CycA-luc alone (1 µg) (lane 1); CycA-luc plus
Tax (2 µg) (lane 2); CycA-luc plus a Tax mutant protein which cannot
bind CREB, TaxH52Q (2 µg) (lane 2) (22); CycA-luc plus
TAFII250 (2 µg) (lane 4); CycA-luc plus
TAFII250 and Tax (2 µg) (lane 5); or CycA-luc plus
TAFII250 and TaxH52Q (2 µg) (lane 6). (B) ts13 cells were
transfected with a luciferase reporter containing either an HTLV-1 LTR
promoter (LTR-luc) (lanes 1 to 3) or an NF-B-responsive promoter
(pNFB-luc) (lanes 4 to 6). Transfections were with the reporter
alone (0.5 µg) (lanes 1 and 4), the reporter plus Tax (0.5 µg)
(lanes 2 and 5), or the reporter plus TaxH52Q (0.5 µg) (lanes 3 and
6). (C) ts13 cells were transfected with either DPA-luc (wild-type
promoter; lanes 1 to 4) or DPAATF-luc (promoter with the ATF site
deleted; lanes 5 to 8). Transfections were with DPA-luc alone (1 µg)
(lane 1), DPA-luc plus increasing amounts of Tax (lanes 2 to 4),
DPAATF-luc alone (1 µg) (lane 5), or DPAATF-luc plus increasing
amounts of Tax (lanes 6 to 8). (D) ts13 cells were transfected
with DPA-luc (lanes 1 to 4) or DPAATF-luc (lanes 5 to 8).
Transfections were with DPA-luc alone (1 µg) (lane 1), DPA-luc plus
increasing amounts of TaxV89A (lanes 2 to 4), a Tax point mutant
protein with wild-type CREB-binding activity (28),
DPAATF-luc alone (5 µg) (lane 5), or DPAATF-luc plus increasing
amounts of TaxV89A (lanes 6 to 8). Results are averages from three
independent experiments (A and D).
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The involvement of CREB/ATF in repression was further analyzed using
CREB/ATF binding site-intact or CREB/ATF binding site-deleted
(DPA
ATF-luc) forms of DPA-luc. In these assays, we tested both
Tax
(Fig.
4C) and a Tax point mutation protein, TaxV89A, which
binds CREB
with wild-type affinity (Fig.
4D). Figure
4D shows
that in contrast to
TaxH52Q, TaxV89A effectively repressed DPA-luc
(Fig.
4D, lanes 2 to 4).
On the other hand, CREB/ATF-independent
expression from DPA
ATF-luc
(Fig.
4C and D, lanes 6 to 8) was
insignificantly affected by either
Tax or TaxV89A. Collectively,
the results in Fig.
4A, C, and D verify
that Tax interferes with
CREB/ATF-dependent activity at the cyclin A
and DNA polymerase
promoters and that this interference correlates
with the ability
of Tax to bind
CREB.
Tax repression does not require CBP binding.
It has been shown
that optimal Tax function requires binding not only to CREB but also to
CREB-binding protein (CBP) (20). Interestingly, Tax
sequestration of CBP has also been proposed as a mechanism which
explains the repression of MyoD-dependent (63) and
p53-dependent (85) transcription. In view of these findings, we wished to clarify whether repression of the cyclin A, DNA
polymerase , and cyclin D3 promoters was also a consequence of CBP
binding by Tax. To address this question, we interrogated the
activities of two Tax mutant proteins, TaxL90A and TaxV89A, in ts13
cells. TaxL90A and TaxV89A have been characterized for binding to CBP
(28); the former binds CBP with wild-type affinity, while
the latter (although intact for CREB binding) binds CBP negligibly.
When these two mutant proteins were tested, both were found to repress
indistinguishably the cyclin A (Fig. 5A)
and the cyclin D3 (Fig. 5B) promoters. Similar repression was also observed for both TaxL90A and TaxV89A on the DNA polymerase promoter (data not shown). These findings clarify that Tax repression of the cyclin A and cyclin D3 promoters does not require CBP binding.
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FIG. 5.
Tax represses expression of cyclin A and cyclin D3
promoters through a CBP-independent mechanism. (A) ts13 cells were
transfected with CycA-luc alone (1 µg) (lane 1) or CycA-luc plus
increasing amounts (as indicated) of either TaxL90A (lanes 2 to 4) or
TaxV89A (lanes 5 to 7). (B) The same transfections were repeated using
CycD3-luc. Note that TaxL90A is functionally and physically intact for
interaction with CBP but that TaxV89A is deficient in both respects.
Results are averages from two independent experiments.
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Tax affects protein complex formation at the CREB/ATF binding
site.
The HTLV-1 LTR contains three CREB/ATF binding sites
(37). Highly efficient activation of this viral LTR by Tax
is, in part, explained by Tax-CREB complex formation at cognate sites
in the LTR (23, 46, 59). This ability of Tax to activate
transcription via CREB/ATF sites is context specific since at other
CREB binding sites (i.e., those found in cellular promoters), Tax-CREB
complex formation may occur (46, 59, 77), but no
activation is seen. The above CycA-luc, DPA-luc, and CycD3-luc results
are compatible with an alternative functional interpretation: Tax-CREB
interaction at some TATA-less promoters manifests as repression.
To check that functional repression by Tax correlates with
"altered" protein complex formation at CREB/ATF sites, we performed
EMSAs using nuclear extracts from several T-cell lines (Jurkat,
C8166-45, MT4, uninduced JPX9, and metal-induced JPX9 cells).
Jurkat is
a well-established T-cell line whose transformation
is unrelated
to HTLV-1. C8166-45 (
64) and MT4 (
53)
are HTLV-1-transformed
T cells which express Tax constitutively. JPX9
cells are derived
from Jurkat cells and contain an integrated Tax gene
under the
control of a metal-inducible metallothionein promoter
(
58) (Fig.
6D). Using these
extracts, we examined complex formation with
either a probe which
contains the sequence of the ATF element
from the cyclin A promoter
(Fig.
6A, lanes 1 to 4, and C, lanes
1 to 2) or a second probe which
contains a mutated ATF sequence
(mATF) (Fig.
6A, lanes 5 to 8, and C,
lanes 3 to 4). Comparing
ATF to mATF (Fig.
6A and B), we could resolve
three sequence-specific
moieties (I, II, and III,) together with
several nonspecific bands.
Among the three sequence-specific complexes,
the profiles of bands
II and III changed when Tax-expressing C8166-45
cells or MT4 cells
were compared to Jurkat cells. When JPX9 cells were
induced with
zinc to express Tax (Fig.
6C, lane 2), corresponding
changes in
the moiety II and III complexes were also noted (Fig.
6C,
lanes
1 and 2). In both instances, Tax expression led to an enhanced
band II and a reduced prominence in band III. A complex formed
on a
probe containing the TdT Inr sequence was used as a parallel
control to
indicate that equivalent concentrations of nuclear
factors were used
for the Jurkat, C8166-45, and MT4 extracts (Fig.
6A, lanes 9 to 12).
Addition of anti-Tax antibody to the C81 nuclear
extract prior to
addition of the labeled probe resulted in a shift
of band II (data not
shown), consistent with the presence of Tax
protein in this complex.
These results are compatible with an
interpretation that Tax affects
the composition of a complex(es)
formed at the cyclin A-derived
CREB/ATF site.
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|
FIG. 6.
Tax affects protein-DNA complexes formed at the
cyclin A promoter. (A) EMSA using an ATF binding site probe. Nuclear
extracts, as indicated, were incubated with labeled probes consisting
of either the wild-type ATF binding site (lanes 1 to 4), mATF (lanes 5 to 8), or a TdT promoter sequence (as a parallel control to indicate
factor concentration of extracts; lanes 9 to 12). Probe alone is shown
in lanes 1, 5, and 9. (B) EMSA using an ATF plus Inr probe derived from
the cyclin A promoter. Probe alone is shown in lanes 1 and 5. (C) EMSA
using the ATF probe (lanes 1 to 2), the mATF probe (lanes 3 to 4), and
the ATF plus Inr probe (lanes 5 to 8) in nuclear extracts of JPX9 cells
(lanes 1 to 4 and 7 to 8), which were either uninduced or induced with
ZnCl2 or Jurkat cells (lanes 5 to 6) that had or had not
been induced with ZnCl2. (D) Western blot of cells using
anti-Tax serum. C8166-45 and MT4 cells express Tax constitutively, JPX9
cells induced with 120 µM ZnCl2 express Tax, and Jurkat
cells and uninduced JPX9 cells do not express Tax. Note that we have
consistently observed a difference in the migration size of the Tax
protein from JPX9 cells. An explanation for this is currently unknown.
(E) Sequences of probes are shown with the ATF site in bold (wild type
or mATF) and the Inr underlined; the transcription start site is
denoted by asterisk.
|
|
We next used an EMSA probe which included both the ATF binding site and
the Inr sequence from the cyclin A promoter (
30).
With the
longer probes, resolution of protein-DNA complexes was
less distinct.
Nevertheless, the protein-DNA complexes formed
on the ATF-Inr probe
using nuclear extracts from two Tax-expressing
cell lines (C8166-45 and
MT4 cells) (Fig.
6B, lanes 2 and 3) were
clearly different from those
formed using a non-Tax-expressing
extract (Jurkat) (Fig.
6B, lane 4).
Changes in complex formation
on this probe were also apparent when we
compared uninduced JPX9
cells to induced JPX9 cells (Fig.
6C, lanes 7 to 8). This change
was not a consequence of zinc induction, as no
change was detected
in nuclear extracts of Jurkat cells induced with
ZnCl
2 (Fig.
6C,
lanes 5 to 6). While we do not fully
understand why complexes
form differently in the various extracts, the
results collectively
support an interpretation that these are
Tax-mediated
changes.
Reduced cyclin A expression in Tax-expressing and in
HTLV-1-transformed cells.
From several perspectives, the above
findings would be fully compatible with perturbed cyclin A expression
in Tax-expressing and in HTLV-1-transformed cells. Levels of cyclin A
protein normally oscillate during the cell cycle, with rapid
accumulation at the beginning of S phase (reviewed in reference
42). To examine at the intracellular level Tax effects on
cyclin A in early S phase of the cell cycle, we synchronized JPX9 and
Jurkat cells using a double thymidine block protocol which enriches for
nascent S cells (reviewed in reference 75). Cells released
from the double thymidine block commence to progress from
G1 into S. Cyclin A expression in thusly processed cells
was monitored for JPX9 (Fig. 7A, lanes 1 to 5), as well as JPX9 cells treated with zinc to express Tax (Fig. 7A,
lanes 1 and 6 to 9). As controls, Jurkat cells, untreated (Fig. 7B,
lanes 1 to 5) or treated with zinc (Fig. 7B, lanes 1 and 6 to 9), were
also assessed to determine any effects which might occur solely from
zinc treatment.
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|
FIG. 7.
Expression of Tax is correlated with reduced expression
of cyclin A in synchronized T cells. (A) JPX9 cells were synchronized
with a double thymidine block. One set of uninduced cells was harvested
at 0, 6, 12, 18, or 24 h after release from the block (lanes 1 to
5). A second set was induced with 120 µM ZnCl2 at time
zero after release and harvested at the same time points (lanes 6 to
9). (B) Jurkat cells were treated as described for panel A for JPX9.
Samples in panels A and B were probed with specific antisera to cyclin
A, -actin, and Tax. (C) Graphic quantitation of relative levels of
cyclin A and Tax synthesis in cells. -Actin bands were measured by
densitometery (a lighter exposure was used for the JPX9 cells), and the
values were used to normalize for densitometric quantitations of cyclin
A and Tax. Results for cyclin A (bars; left y axis) are
shown quantitatively as percentages of increase over the amount at time
zero. Tax (line; right y axis) expression in induced JPX9
cells is shown in arbitrary densitometric units.
|
|
Cyclin A expression was assessed by immunoblotting using specific
antiserum. On the same blots, we also checked for expression
of Tax
(Fig.
7A) and the cellular
-actin protein (Fig.
7A and
B). Signals
were quantitated by densitometry, and values were
normalized to those
for
-actin (Fig.
7C). Based on quantitations
from the Western blots,
we deduced that cyclin A levels increased,
as expected, in Jurkat and
JPX9 cells as the cells entered into
S phase (Fig.
7C). Zinc treatment
of Jurkat cells had an unexpected
effect of enhancing cyclin A
expression. However, zinc treatment
of JPX9 cells (which clearly
induced Tax expression [Fig.
7A,
lanes 6 to 9]) had a markedly
suppressed cyclin A expression (Fig.
7C). Thus, whereas zinc treatment
nonspecifically enhanced cyclin
A in Jurkat cells, the same treatment
in JPX9 cells distinctly
established Tax expression with cyclin A
suppression.
The correlation between Tax expression and cyclin A
repression in JPX9 cells prompted us to investigate authentically
HTLV-1-transformed
cell lines. We compared cyclin A expression in
Jurkat, HeLa, and
four HTLV-1 cell lines: C8166-45, MT4, ILT-Hod, and
TL-Su. MT4
and C8166-45 were derived from coculture of human cord
leukocytes
and HTLV-1-infected cells (
53,
64). TL-Hod was
derived from
an ATL patient (
3), while TL-Su was derived
from an HTLV-1
carrier (
3). Immunoblotting with cyclin
A-specific serum showed
that amounts of cyclin A were greatly reduced
in all four HTLV-1-positive
cells (Fig.
8A, lanes 3 to 6) when compared to the
amount in Jurkat
(Fig.
8A, lane 2) or HeLa (Fig.
8A, lane 1) cells. In
Fig.
8B,
cyclin A expression values are graphed after normalization to
-actin values. These results, together with a previous report
of a
reduced level of cyclin A mRNA in HTLV-1-infected T-cell
lines
(
2), are consistent with reduced cyclin A as a
characteristic
of HTLV-1 infection and transformation.
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|
FIG. 8.
HTLV-1-transformed cells express reduced amounts of
cyclin A compared to levels expressed in HeLa and Jurkat cells. ILT-Hod
and TL-Su are cell lines established from ATL patients; C8166-45 and
MT4 cells are derived from in vitro cocultivation of cord blood with
HTLV-1 producer cells. (A) Representative Western blot of the indicated
cells; (B) quantitation of amounts of cyclin A after normalization to
-actin amounts. Mol Wt, molecular weight.
|
|
| |
DISCUSSION |
Viruses are obligatory host cell parasites. Consequently, it is
not surprising that the life cycles of viruses importantly depend on
the cell cycle of the host. Parvoviruses, for example, rely on the host
cell S phase to replicate viral-DNA genomes (14). Herpesviruses interact with several cyclins and cyclin-dependent kinases, implicating critical participation by these cell cycle proteins in virus expression and replication (66, 86). The human immunodeficiency virus utilizes the host G1 phase to
complete reverse transcription and to prepare for integration of its
proviral genome (76, 94), and emerging evidence indicates
that the HTLV-1-encoded Tax protein plays important roles in modulating cell cycle progression (reviewed in reference 55). Here,
we unexpectedly found that the levels of an S- and M-phase cyclin, cyclin A, is repressed by HTLV-1 Tax.
Expression of Tax by HTLV-1 has been correlated with cellular
transformation (62; reviewed in reference
91). Arguably, effects of Tax on cell cycle progression
are important to the transforming biology of HTLV-1. Historically, Tax
was first characterized as a potent activator of gene expression
(reviewed in reference 91). Hence, the ability by Tax to
activate mitogenic factors such as IL-2 (34, 73), IL-2
receptor (5), Jun (19), and Fos
(18) was predictable and is fully compatible with its expected cell growth-promoting phenotype. Recently, it has, however, become apparent that several prototypic transcriptional gene activators such as p53 (21, 35, 50), E2F (96), and E1a
(6, 47) are also potent transcriptional repressors of
other genes. Thus, it is suggested that the ambient outcomes of
transactivator proteins reflect the collective balance of up- and
down-regulatory effects on different subsets of genes. Indeed, for
HTLV-1 Tax, the initial suggestion of its potential as a
trans-repressor (39) has been rapidly extended
by a flurry of studies describing its repressive activity on factors
such as p53 (84), p16INK4a (49, 79), lck
(48), p18INK4c (80), c-Myc (69),
MAD1 (41), and c-Myb (57), among others.
In considering transcriptional repression by Tax, there are currently
two proposed mechanisms. First, a series of examples indicate that Tax
works repressively through its interaction with an E-box-binding
basic-helix-loop-helix protein (39, 48, 63, 69, 78, 80,
84). Second, other studies support mechanistic repression by Tax
through its sequestration of p300/CBP coactivator proteins (4,
78, 85). Here, our descriptions of the cyclin A, cyclin D3, and
DNA polymerase promoters suggest a third route through which Tax
manifests transcriptional repression: context-specific binding to
CREB/ATF.
Several findings helped us define the mechanism utilized by Tax to
repress the promoter activities of cyclin A, cyclin D3, and DNA
polymerase . Initially, we observed that Tax proteins competent for
CREB binding (e.g., wild-type Tax and TaxV89A) exhibited repression but
that a Tax mutant protein (TaxH52Q) which cannot bind CREB failed to
exert this repression (Fig. 4A). Next, that DPA-luc, but not
DPAATF-luc, was repressed by Tax delineated a requirement for
CREB/ATF in this repressive process (Fig. 4C and D). Last, similarly to
another example of the down-regulation of the cyclin A promoter through
its upstream CREB/ATF site (92), we found distinct changes
in protein-DNA complex formation when using CREB/ATF-motif-containing
probes to compare nuclear extracts with or without Tax (Fig. 6). These
observations, coupled with the demonstration that cyclin A, cyclin D3,
and DNA polymerase repression is CBP independent (Fig. 5), provided
a first illustration of Tax-mediated repression through
context-specific sequestration of CREB/ATF. We note that in other
systems, context-specific activation and repression is not without
precedent. For instance, at many promoters the YY1 protein activates
transcriptional initiation by stimulating recruitment of RNA polymerase
II while at other promoters YY1 represses transcription by sequestering
CREB/ATF (95). Similarly, depending on context, the cyclin
A gene has also been shown to be either up- or down-regulated through
its upstream CREB/ATF site (15, 16, 92, 93).
How might HTLV-1 benefit from repressed expression of cyclin A? In
relevant T-cell lines, we clearly observed that amounts of cyclin A are
significantly reduced both by HTLV-1 transformation (Fig. 8) and by the
singular expression of Tax (Fig. 7). These findings agree with a
previous report of reduced cyclin A mRNA in HTLV-1-infected T-cells
(2). Interestingly, in other virological settings, cyclin
A is similarly repressed by cytomegalovirus (36, 65) and
herpes simplex virus (1) infection of cells. While we do
not fully understand why viruses should repress cyclin A, a few
thoughts come to mind. First, we note that cyclin A negatively regulates E2F-1 activity (45) during the S phase of the
cell cycle. One speculation is that reduced amounts of cyclin A result in a prolonged S phase, which thereby benefits the replication of viral
genomes. Second, a role in preventing aberrant reassembly of DNA
initiation complexes in the S phase of the cell cycle was recently
further attributed to cyclin A-cdk2 (12). In this
perspective, normal cyclin A-cdk2 activity ensures that only one round
of DNA replication occurs within a single S phase. Considered thusly, Tax repression of cyclin A may engender aberrant DNA reduplication, providing another explanation for how this oncoprotein induces aneuploidogenic abnormalities in cells (reviewed in reference 43). Finally, in its role as a mitotic cyclin, cyclin A
also regulates egress of cells from mitosis (74, 87).
Suppression of cyclin A may result in accelerated progression through
mitosis, further accounting for the failure in HTLV-1-transformed cells to faithfully execute the mitotic spindle assembly checkpoint (41).
The unexpected observation that Tax represses cyclin A provides a
further illustration of the intimate relationship between viruses and
host factors. It additionally highlights the delicate balance between
positive and negative events in maintaining cellular homeostasis. Our
Tax-cyclin A results add to the growing literature stating that this
cyclin is commonly targeted by viruses. Thus, HTLV-1 joins adenovirus
(61), HBV (90), and herpesviruses (1) in subverting the function(s) of cyclin A. Future
studies on virus-cyclin interplays are likely to advance our
understanding of the symbiosis between viruses and cells.
| |
ACKNOWLEDGMENTS |
We thank Hidekatsu Iha, Yoichi Iwanaga, Takefumi Kasai, Yalin Wu,
and Venkat Yedavalli for critical readings of the manuscript; Lan Lin
for help in the preparation of the manuscript; Alicia Buckler-White for
oligonucleotide synthesis; and M. Kannagi, M. Fujii, T. Wang, K. Peden,
C. Z. Giam, P. Hinds, and R. Tjian for gifts of reagents.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: LMM/NIAID/NIH,
Building 4, Room 306, 4 Center Dr., MSC 0460, Bethesda, MD 20892-0460. Phone: (301) 496-6680. Fax: (301) 480-3686. E-mail:
kjeang{at}niaid.nih.gov.
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Abstract
Introduction
