Previous Article | Next Article 
Journal of Virology, October 2001, p. 9571-9578, Vol. 75, No. 20
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.20.9571-9578.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
The Bovine Herpesvirus 1 Immediate-Early Protein
(bICP0) Associates with Histone Deacetylase 1 To
Activate Transcription
Yange
Zhang and
Clinton
Jones*
Department of Veterinary and Biomedical
Sciences, Center for Biotechnology, University of Nebraska,
Lincoln, Nebraska 68503
Received 9 July 2001/Accepted 13 July 2001
 |
ABSTRACT |
Infected-cell protein 0 encoded by bovine herpesvirus 1 (BHV-1)
(bICP0) is necessary for efficient productive infection, in large part, because it activates all 3 classes of BHV-1 genes (U. V. Wirth, C. Fraefel, B. Vogt, C. Vlcek, V. Paces, and M. Schwyzer,
J. Virol. 66:2763-2772, 1992). Although bICP0 is
believed to be a functional homologue of herpes simplex virus type
1-encoded ICP0, the only well-conserved domain between the proteins is
a zinc ring finger located near the amino terminus of both proteins. Our previous studies demonstrated that bICP0 is toxic to
transfected cells but does not appear to directly induce apoptosis
(Inman, M., Y. Zhang, V. Geiser, and C. Jones, J. Gen.
Virol. 82:483-492, 2001). C-terminal sequences in the last 320 amino
acids of bICP0 mediate subcellular localization.
Mutagenesis of the zinc ring finger within bICP0 revealed
that this domain was important for transcriptional activation. In this
study, we demonstrate that bICP0 interacts with histone
deacetylase 1 (HDAC1), which results in activation of a simple promoter
containing four consensus Myc-Max binding sites. The interaction
between bICP0 and HDAC1 correlated with inhibition of
Mad-dependent transcriptional repression. In resting CV-1 cells,
bICP0 relieved HDAC1-mediated transcriptional repression. The
zinc ring finger was required for relieving HDAC1-induced repression
but not for interacting with HDAC1. In fetal bovine lung cells but not
in a human epithelial cell line, bICP0 expression correlated
with reduced steady-state levels of HDAC1 in crude cytoplasmic
extracts. We hypothesize that the ability of bICP0 to
overcome HDAC1-induced repression plays a role in promoting productive
infection in highly differentiated cell types.
| |
INTRODUCTION |
Bovine herpesvirus 1 (BHV-1)
infection can cause conjunctivitis, pneumonia, genital disorders,
abortions, and an upper respiratory infection referred to as shipping
fever (61). Infection of permissive cells with BHV-1 leads
to rapid cell death, in part due to apoptosis (12). Viral
gene expression is temporally regulated in three distinct phases:
immediate-early (IE), early (E), and late (L). IE transcription unit 1 (IEtu1) encodes a transcriptional activator, bICP0 (65,
66). Although bICP0 is believed to be a functional homologue of herpes simplex virus type 1 (HSV-1)-encoded ICP0, the only
well-conserved domain is a C3HC4 zinc ring
finger located near the N terminus of both proteins (14-17,
46). Most alphaherpesviruses encode a bICP0-like
transcriptional activator that contains a zinc ring finger domain
(46). These ICP0 homologues transactivate all classes of
viral genes (4, 22, 39, 40, 45), demonstrating they are
promiscuous trans-activators. Mutational analysis has demonstrated the importance of the zinc ring finger domain in HSV-1
ICP0 (14-17, 46), equine herpesvirus 1 ICP0-like
protein (EICP0) (4, 5), and BHV-1 bICP0
(35). Zinc ring finger domains are believed to
mediate protein-protein interactions (P. S. Freemont, I. M. Hanson, and J. Trowsdale, Letter, Cell
64:483-484), suggesting that the ability of
bICP0 to interact with other proteins is important for
efficient productive infection in nondividing cells.
ICP0 (18-20, 51, 52) and bICP0 (35,
55) colocalize with and disrupt the proto-oncogene
promyelocytic leukemia protein-containing nuclear domains (ND10 or
PODS). ICP0 can regulate the stability of cellular and viral proteins
by interacting with the protein degradation machinery (18,
20). For example, the stability of the catalytic subunit of
DNA-dependent protein kinase is regulated by ICP0 (44,
56). ICP0 also binds cyclin D3 (38) and elongation factor delta (37). The results of these interactions are
perturbation of the cell cycle and altered cellular gene expression
(p21, gadd45, and mdm-2, for example) (30). Interestingly,
a histone deacetylase (HDAC) inhibitor, trichostatin A, and ICP0 have
similar effects on cellular and viral gene expression
(30).
Numerous studies have demonstrated that histone acetylases (HAT) and
histone deacetylases (HDAC) play an important role in transcriptional
regulation by affecting chromatin assembly, transcription factor
accessibility, and nucleosome remodeling (24). Several families of acetylases have been identified, including PCAF/GCN5, p300/CBP, TAF250, SRC1, and MOZ (42). HAT can also
acetylate other transcription factors (34), including
p53 (25), E2F1 (50), EKLF (67),
TFIIEa, TFIIF, TCF (64), GATA1 (6), HMGI(Y)
(54), ACTR (9), and high-mobility group
protein HMG-1 (60). Acetylation regulates many diverse
functions, including DNA recognition, protein-protein
interaction, and protein stability. To date, six human HDAC have been
identified (21, 23, 41, 53, 63). In mammalian cells, HDAC1
and HDAC2 are found in two complexes: the mSinA corepressor
complex and the nucleosome-remodeling HDAC complex (NuRD)
(28). The mSin3A-HDAC complex is recruited to DNA by
Mad1 to repress transcription in an HDAC-dependent manner. HDAC
is also recruited to specific promoter regions by other transcription factors such as Rb (48, 49), Sp1 (13), and
YY1 (10). These interactions lead to chromatin
deacetylation and transcriptional repression.
A previous study demonstrated that expression of the proto-oncogene
myc was stimulated following infection of peripheral blood mononuclear cells with BHV-1 (26). The induction of Myc is
consistent with cell cycle alterations and apoptosis after infection.
The Myc protein dimerizes with Max and binds to a specific
cis-acting element (CACGTG), which leads to
activation of transcription. Myc plays a central role in regulating
cell proliferation and apoptosis (58). Conversely, Mad
dimerizes with Max, recognizes the same consensus DNA sequence as
Myc-Max, and represses transcription. Mad is induced on differentiation
of a number of distinct cell types (1, 3, 32, 33). The
switch from growth-promoting Myc-Max to growth-inhibiting Mad-Max
results in a transition from cellular proliferation to differentiation.
Transcriptional repression by Mad-Max heterodimers is mediated by
ternary-complex formation with corepressor mSin3 and HDAC activity
(27, 43).
In this study, we investigated the ability of bICP0 to
activate transcription. We demonstrated that C-terminal sequences and a
functional zinc ring finger domain were required for transactivation of
a minimal HSV-1 thymidine kinase (TK) promoter. bICP0
interacted with HDAC1, but not with cyclin-dependent kinase 2 (cdk2),
in transiently transfected cells. The interaction with HDAC1 correlated with relief of Mad- and HDAC1-mediated transcriptional
repression. HDAC1-induced transcriptional repression was observed
in serum-arrested cells but not actively growing cells, suggesting that
bICP0, in part, stimulates productive infection in
differentiated cells by interacting with HDAC1.
| |
MATERIALS AND METHODS |
Cells and plasmids.
CV-1 cells (African green monkey kidney
cells) and human epithelial 293 cells were grown in Earle's modified
Eagle's medium supplemented with 5% fetal bovine serum. Bovine fetal
lung (BFL) cells were grown in the same medium with 10% fetal bovine serum.
pCMV-bICP0 contains the bICP0 coding sequences
under the control of the human cytomegalovirus (CMV) promoter.
Mutagenesis of the bICP0 zinc ring finger was described
previously (35). The coding regions of the wild-type
bICP0 and the zinc ring finger mutant 13G/51A were inserted
into Flag-tagged expression vectors pCMV2C (bICP0) or pCMV4B
(13G/51A), respectively (Stratagene, San Diego, Calif.). A C-terminal
deletion of bICP0 (amino acids 356 to 676;
bICP0) was generated by deleting the
SalI-XhoI fragment from the Flag-tagged
bICP0 construct. For a summary of these constructs, see Fig.
6.
pCMV-Mad is a CMV expression plasmid that expresses Mad in mammalian
cells and was obtained from D. Ayer (University of Utah,
Salt Lake
City). pCMV-HDAC1 is a CMV expression plasmid that
expresses
HDAC1 in mammalian cells and was obtained from T. Kouzarides
(Wellcome/CRC
Institute, Cambridge, United Kingdom). pSV2cat contains
the simian
virus 40 early promoter and enhancer and was obtained from
B.
Howard (National Institutes of Health). pHIVcat contains a minimal
human immunodeficiency virus promoter (
29 to +84) and was obtained
from C. Wood (Nebraska). pMinCAT contains a minimal HSV-1 TK promoter
TATA box (
32 to +51) and was obtained from L. Kretzner (University
of
South Dakota, Vermillion). pM4minCAT contains four consensus
binding
sites for Mad-Max or Myc-Max that are upstream of the
minimal TK
promoter. pM4minCAT was also obtained from L. Kretzner.
All promoter
constructs were linked to the chloramphenicol acetyltransferase
(CAT)
gene.
Cytoplasmic and nuclear fractionation.
293 or BFL cells were
transfected with 20 µg of the designated bICP0 expression
plasmid. At 40 h after transfection, the cultures were rinsed with
phosphate-buffered saline PBS and harvested. The cell pellet was gently
suspended in hypotonic lysis buffer (10 mM HEPES [pH 7.9], 10 mM KCl,
3 mM MgCl2, 1 mM EDTA, 1 mM dithiothreitol [DTT], 0.05%
NP-40, complete proteinase inhibitors [Roche Molecular Biology; 1 tablet/10 ml]). The cell suspension was incubated at 4°C for 30 min
and then centrifuged at 2,500 rpm for 5 min at 4°C in a
Beckman Avanti 30 centrifuge. The supernatant (cytoplasmic fraction)
was transferred to a new tube and stored at 80°C. The nuclear
pellet was washed in hypotonic lysis buffer once and centrifuged as
above. The crude nuclei were incubated with high-salt buffer (50 mM
HEPES [pH 7.9], 250 mM KCl, 0.1 mM EDTA, 5% glycerol, 1 mM DTT,
0.1% NP-40, complete proteinase inhibitors)at 4°C for 30 min. The
lysate was then centrifuged at 15,000 rpm for 10 min at 4°C in
a Beckman Avanti 30 centrifuge, and the supernatant (nuclear fraction)
was stored at 80°C.
Western blot analysis.
293 cells were transfected with 20 µg of the designated bICP0 expression plasmid by calcium
phosphate precipitation (68). At 40 h after
transfection, cells were collected and lysed in 500 µl of 1× SDS
sample buffer (50 mM Tris-HCl [pH 6.8], 10% glycerol, 2% sodium
dodecyl sulfate [SDS], 5% 
-mercaptoethanol). The cell extract was
boiled for 5 min. and the supernatant was used for SDS-polyacrylamide
gel electrophoresis. Immunodetection of bICP0 and its mutants
was performed with an anti-Flag monoclonal antibody (Stratagene no.
200471-21). HDAC1 protein expression was detected with an anti-HDAC1
antibody (Santa Cruz no. sc-7872).
Analysis of CAT enzymatic activity in transiently transfected
cells.
Transfection and CAT assays were described previously
(68). Briefly, 15 µg of reporter construct and 6 µg of
bICP0 expression plasmid were cotransfected into CV-1 cells
by the calcium phosphate precipitation method. At 48 h after
transfection, the cells were lysed and CAT activity was measured.
Chloramphenicol and its acetylated forms were separated by thin-layer
chromatography. The amount of acetylated chloramphenicol was measured
with a PhosphorImager (Molecular Dynamics, Sunnyvale, Calif.). CV-1
cells were growth arrested by incubating the cultures for 72 h in
medium containing 1% serum (31). Growth-arrested CV-1
cells were cotransfected with 15 µg of reporter construct, 1.5 µg
of bICP0 expression plasmid, and 0.75 µg of HDAC1
expression vector. At 60 h after transfection, the cells were
lysed and CAT activity was measured. All transfection experiments were
repeated at least three times to confirm the results.
Coimmunoprecipitation assay.
Each Flag-tagged
bICP0 expression vector (20 µg) was transfected into 293 cells (100-mm dish) by calcium phosphate precipitation. At 40 h
after transfection, the cells were collected and suspended in 250 µl
of lysis buffer (20 mM HEPES [pH 7.9], 400 mM KCl, 1.5 mM
MgCl2, 0.2 mM EDTA, 20% glycerol, 0.5 mM DTT, 0.5 mM
phenylmethylsulfonyl fluoride, 5 µg of leupeptin per ml, 5 µg of
pepstatin per ml, 5 µg of antipain per ml). The whole-cell lysate was
sonicated and centrifuged for 10 min at 4°C (15,000 rpm) in a
Beckman Avanti 30 centrifuge. The supernatant was diluted to 1 ml with
the same lysis buffer but containing 20 mM KCl. A 10-µl sample of
normal mouse serum and 40 µl of protein A-agarose were then added.
The mixture was incubated at 4°C for 1 h and centrifuged at
2,500 rpm in a Beckman Avanti 30 centrifuge for 5 min to pellet
the beads. The supernatant was then incubated with 2 µg of the
anti-HDAC1 antibody at 4°C for 1 to 3 h. Protein A-agarose beads
(40 µl) were added, and the mixture was incubated at 4°C on a
rotating device overnight. The beads were collected by centrifugation
at 2,500 rpm for 5 min in a Beckman Avanti 30 centrifuge and
washed four times with wash buffer (10 mM Tris-HCl [pH 8.0], 50 mM
NaCl, 1 mM EDTA, 0.5% NP-40). After a final wash, the beads were
suspended in 40 µl of 1× sample buffer and boiled for 3 min.
Immunodetection of the precipitated protein was performed using the
anti-Flag antibody. Reciprocal immunoprecipitations were also
performed. Briefly, 20 µg of each Flag-tagged bICP0
expression vector was transfected into 293 cells. Anti-Flag antibody
conjugated to agarose beads (40 µl; Sigma no. A-1205) was used for
the immunoprecipitation. Western blot analysis was performed using
anti-HDAC antibody.
| |
RESULTS |
bICP0 can activate non-BHV-1 promoters.
bICP0 can stimulate IE, E, and L BHV-1 promoters,
demonstrating that bICP0 is a "promiscuous"
trans-activator (22, 39, 40). To further
evaluate the ability of bICP0 to activate transcription, we
tested its ability to activate promoters that are not present in the
BHV-1 genome. CV-1 cells were cotransfected with bICP0 expression plasmids and CAT promoter constructs containing the simian
virus 40 early promoter-enhancer (pSV2cat), a minimal HIV promoter
(29 to +84; pHIVcat), or a minimal HSV-1 TK promoter (32 to
+51; pMinCAT) (Fig. 1A). bICP0
transactivated pHIVcat and pMinCAT promoter activity more than 10-fold
(Fig. 1B). It also stimulated pSV2cat promoter activity, but to a
lesser extent. This study demonstrated that bICP0 has the
ability to efficiently transactivate promoters that are not derived
from BHV-1.
View larger version (58K):
[in this window]
[in a new window]
|
FIG. 1.
bICP0 can trans-activate several
different promoters. The designated CAT reporter constructs (15 µg of
DNA) were cotransfected with 6 µg of pCMV-bICP0 or a blank
expression vector (V) into CV-1 cells. CAT activity was measured at
48 h after transfection by incubating cell-free lysate with
[14C]chloramphenicol (CM) for 3 h. These results
are representative of three independent experiments.
|
|
bICP0 activates a promoter containing four Myc-Max
binding sites.
A previous study demonstrated that BHV-1 infection
induces c-Myc expression in peripheral blood mononuclear cells
(26). Since bICP0 is a promiscuous
transcriptional activator, we tested whether bICP0 activated
c-Myc-dependent transcription. A reporter construct that contains four
consensus binding sites for Myc-Max (or Mad-Max) upstream of a minimal
TK promoter was used for this study (pM4minCAT) (Fig.
2A). CV-1 cells were cotransfected with one of the bICP0 expression plasmids and pM4minCAT or, as a
control, pMinCAT. CAT activity was measured at 48 h after
transfection. bICP0 and bICP0, but not the zinc
ring finger mutant protein (13G/51A), stimulated M4 promoter activity
(Fig. 2B). Although bICP0 was capable of
trans-activating the minimal TK promoter (pMinCAT),
bICP0 and 13G/51A did not (Fig. 2C). bICP0
trans-activated pM4minCAT more efficiently than it
trans-activated pMinCAT (approximately 35-fold versus
4-fold), suggesting that it had an effect on c-Myc-dependent transcription.
View larger version (43K):
[in this window]
[in a new window]
|
FIG. 2.
bICP0 activates a promoter containing four Myc
binding sites. (A) pM4minCAT is a plasmid containing four consensus
Myc-Max or Mad-Max binding sites upstream of a minimal HSV-1 TK
promoter. (B) CV-1 cells were cotransfected with 15 µg of pM4minCAT
and 6 µg of vector, bICP0, bICP0, or 13G/51A
expression plasmid. (C) CV-1 cells were cotransfected with 15 µg of
reporter construct (pMinCAT), which contains the minimal HSV-TK
promoter, and 6 µg of vector, bICP0, bICP0, or
13G/51A expression plasmid. At 48 h after transfection, CAT
activity was measured by incubating cell-free lysate with
[14C]chloramphenicol (CM) for 1 h. The results are
representative of three independent experiments.
|
|
bICP0 relieves Mad-mediated repression.
Myc-dependent transcription is regulated by several distinct mechanisms
(1, 2). Myc-Max heterodimers bind to consensus Myc binding
sites and activate transcription. Conversely, Mad-Max heterodimers bind
to the same sequence and repress transcription, in large part, because
Mad is associated with HDAC1 (3, 43, 57). Thus, if
higher concentrations of Myc or lower concentrations of Mad were
present in cells that expressed bICP0, promoter activity of
pM4minCAT would be higher. Transient transfection of CV-1 cells with
increasing amounts of bICP0 did not dramatically increase c-Myc protein levels or reduce Mad protein levels (data not shown).
To determine whether bICP0 could relieve Mad-mediated
transcriptional repression, bICP0, a Mad expression vector,
and pM4minCAT
were cotransfected into CV-1 cells. CAT activity was
measured
48 h after transfection. As expected, introducing Mad
into CV-1
cells inhibited pM4minCAT promoter activity
approximately threefold
(Fig.
3).
Wild-type bICP0 and
bICP0 relieved Mad-induced
repression
of pM4minCAT promoter activity. However, the zinc ring
finger
mutant (13G/51A) was not capable of relieving Mad-dependent
repression.
View larger version (58K):
[in this window]
[in a new window]
|
FIG. 3.
bICP0 can relieve Mad-mediated transcriptional
repression. CV-1 cells were cotransfected with 15 µg of pM4minCAT,
1.5 µg of Mad expression plasmid, and 1.5 µg of vector,
bICP0, bICP0, or 13G/51A expression vector. At
48 h after transfection, CV-1 cells were lysed and CAT activity
was measured by incubation with [14C]chloramphenicol (CM)
for 1 h. The results are representative of three independent
experiments.
|
|
bICP0 relieves HDAC1-mediated repression.
To
test whether HDAC1 directly repressed gene expression, we
cotransfected increasing amounts of HDAC1 expression plasmid with pM4minCAT into CV-1 cells. The M4 promoter was not repressed by HDAC1 in actively growing CV-1 cells (Fig.
4A). Two observations led us to
hypothesize that the ability of HDAC1 to function as a transcriptional
repressor might be mediated by cell cycle-specific factors.
First, growing cells normally express high levels of Myc but lower
levels of Mad, suggesting that Myc overcame transcriptional repression of the M4 promoter that was induced by HDAC1. Second, HDAC1
represses cellular TK promoter activity by interacting with Sp1 and
consequently interferes with E2F1 and Sp1 association (13). Since the cellular TK promoter is not active in
serum-arrested cells (G0), a model was developed in which
HDAC1 is proposed to regulate cell cycle-specific transcription of TK.
View larger version (44K):
[in this window]
[in a new window]
|
FIG. 4.
HDAC1 inhibits pM4minCAT promoter activity in resting
CV-1 cells. (A) Actively growing CV-1 cells were cotransfected with 15 µg of pM4minCAT and the designated amounts of HDAC1 expression
plasmid. At 48 h after transfection, the cells were lysed and CAT
activity was measured by incubation with
[14C]chloramphenicol (CM) for 3 h. (B) CV-1 cells
were growth arrested in 1% serum culture medium for 72 h. Then 15 µg of pM4minCAT and the designated amounts of HDAC1
expression plasmid were cotransfected into resting CV-1 cells. At
60 h after transfection, cells were lysed and CAT activity was
measured by incubation with CM for 3 h. The results are
representative of three independent experiments.
|
|
We subsequently determined whether HDAC1 was capable of inhibiting
pM4minCAT promoter activity in quiescent cells by arresting
CV-1 cells
in G
0/G
1 by plating them in 1% serum for
72 h. The
pM4minCAT promoter construct and increasing amounts of
an HDAC1
expression vector were then cotransfected into resting CV-1
cells.
At 60 h after transfection, CAT activity was measured. In
growth-arrested
CV-1 cells, HDAC1 consistently inhibited M4 promoter
activity
by at least twofold (Fig.
4B).
To determine whether bICP0 relieved HDAC1-dependent
repression, bICP0, the HDAC1 expression vectors and pM4minCAT
were cotransfected
into resting CV-1 cells. Wild-type
bICP0 and
bICP0 efficiently
relieved
HDAC1-mediated transcription repression (Fig.
5). In
contrast, 13G/51A was not capable
of
trans-activating pM4minCAT
in the presence of HDAC1,
suggesting that a functional zinc ring
finger domain of
bICP0 was necessary for relieving repression.
In
summary, these results demonstrated that bICP0 transactivated
the pM4minCAT promoter construct by relieving HDAC1- and
Mad-dependent
repression.
View larger version (56K):
[in this window]
[in a new window]
|
FIG. 5.
bICP0 can relieve HDAC1-mediated
transcriptional repression in resting CV-1 cells. CV-1 cells were
growth arrested as described in the legend to Fig. 4B. pM4minCAT (15 µg), 0.75 µg of HDAC1, and 1.5 µg of vector, bICP0,
bICP0, or 13G/51A expression vector were cotransfected
into cultures of resting CV-1 cells. At 60 h after transfection,
the cells were lysed and CAT activity was measured by incubation with
[14C]chloramphenicol (CM) for 3 h. The results are
representative of three independent experiments.
|
|
Analysis of bICP0 protein interaction with HDAC1 in
transiently transfected cells.
We hypothesized that the ability of
bICP0 to relieve HDAC1-mediated repression may be the
result of bICP0 interacting with HDAC1. To test whether
bICP0 interacted with HDAC1 in transiently transfected cells,
we developed Flag-tagged bICP0 expression constructs and
performed immunoprecipitation assays. A deletion mutant lacking the
C-terminal coding region (amino acids 356 to 676) was prepared from the Flag-tagged construct (C terminus), and this construct designated bICP0. Sequential PCR mutagenesis of the
C3HC4 zinc ring finger of bICP0 was
also performed to change cystine-13 to glycine and cystine-51 to
alanine (mbICP0) (35), and this construct is referred to as 13G/51A (Fig. 6B). The
mutations in 13G/51A were predicted to disrupt the zinc ring finger
(46). The coding region of this double mutant was
also cloned into a Flag-tagged expression vector pCMV4B
(Fig. 6A). The Flag-tagged expression vectors were transfected into 293 cells. At 40 h after transfection, cells were lysed and expression
of Flag-tagged bICP0 or its mutant was detected with an
anti-Flag monoclonal antibody. Wild-type bICP0 (Fig. 6C, lane
2) and 13G/51A (lane 4) migrated near 100 kDa when expressed as
Flag-tagged fusion proteins. Deletion of 320 amino acids at
the C terminus (bICP0) resulted in synthesis of a
truncated protein migrating with an apparent molecular mass of
55 kDa (lane 3).
View larger version (28K):
[in this window]
[in a new window]
|
FIG. 6.
Expression of bICP0 constructs as Flag-tagged
proteins. (A) Schematic of wild-type bICP0 and C-terminal
deletion coding sequences. Positions of the zinc ring finger and acidic
domain are shown. (B) Amino acid sequences of the
C3HC4 zinc ring fingers of BHV-1
bICP0 (amino acids 13 to 51) and HSV-1 ICP0 (amino acids 116 to 156). The consensus zinc ring finger sequences are in bold. The
mutations in bICP0 are underlined (amino acid 13 was changed
from C to G, and amino acid 51 was changed from C to A). The methods
used for generating 13G/51A were described previously
(35). (C) 293 cells were transfected with 20 µg of each
Flag-tagged bICP0 expression vector. At 40 h after
transfection, whole-cell lysate was prepared and Western blot analyses
were performed with an anti-Flag antibody. Arrows denote the positions
of the bICP0 and bICP0 proteins. Lanes: 1, transfected with the blank Flag tag expression vector (pCMV2C); 2, transfected with bICP0; 3, transfected with
bICP0; 4, transfected with 13G/51A.
|
|
To test whether bICP0 interacted with HDAC1 or a protein
complex containing HDAC1, Flag-tagged bICP0 was transfected
into
293 cells and HDAC1 was immunoprecipitated at 40 h after
transfection.
The presence of bICP0 in the
immunoprecipitate was tested by Western
blot analysis using a
monoclonal antibody directed against the
flag epitope.
bICP0,
bICP0, and 13G/51A were all
immunoprecipitated
by the HDAC1 antibody (Fig.
7A). Reciprocal immunoprecipitation
experiments confirmed the interaction between bICP0 and
HDAC1.
In contrast, the Flag antibody did not coimmunoprecipitate cdk2,
nor did cdk2 antibodies coprecipitate the respective
bICP0 proteins
(Fig.
7B). In summary, this study demonstrated
that bICP0 interacted
with HDAC1 or an HDAC1-containing
complex in transiently transfected
cells.
View larger version (56K):
[in this window]
[in a new window]
|
FIG. 7.
Interaction between bICP0 and HDAC1. (A)
Cultures of 293 cells were transfected with 20 µg of the indicated
Flag-tagged bICP0 plasmid. At 40 h after transfection,
nuclear extract was prepared. An anti-HDAC1 antibody was used for
immunoprecipitation. The presence of bICP0 and the mutant
proteins was detected with an anti-Flag antibody. Alternatively, 40 µl of anti-Flag antibody-conjugated agarose was used for
immunoprecipitation. The presence of HDAC1 and its expression level in
each transfected cells were detected by a polyclonal antibody
that specifically recognizes HDAC1. (B) 293 cells were transfected with
the designated bICP0 expression vectors, and nuclear extract
was prepared as described for panel A. A 40-µl volume of
anti-cdk2-conjugated agarose was used for immunoprecipitation (IP).
The Western blot analysis (WB) was performed with an anti-Flag
antibody. Reciprocal immunoprecipitation was performed with 40 µl of
anti-Flag-conjugated agarose. The presence of cdk2 and the protein
level of cdk2 in transfected cells were detected with an anti-cdk2
antibody.
|
|
To examine whether bICP0 had any effect on the subcellular
distribution or steady-state levels of HDAC1, 293 or BFL cells
were
transfected with the various bICP0 Flag-tagged constructs
and
HDAC1 protein levels were measured by Western blot analysis.
This study
demonstrated that in BFL cells, bICP0 reduced HDAC1
protein
levels in cytoplasmic extracts but not nuclear extracts
(Fig.
8). No differences in cdk2 levels were
detected in cells
transfected with bICP0. In 293 cells,
bICP0 did not have any effect
on HDAC1 protein levels (data
not shown).
View larger version (23K):
[in this window]
[in a new window]
|
FIG. 8.
The cytoplasmic HDAC1 level is reduced in BFL cells
transiently transfected with bICP0 expression plasmids. 293 cells and BFL cells were transfected with the designated Flag-tagged
bICP0 expression vector. At 40 h after transfection,
cytoplasmic and nuclear fractions were prepared and Western blot (WB)
analysis was performed using an anti-HDAC1 antibody or an anti-cdk2
antibody.
|
|
| |
DISCUSSION |
bICP0 is a promiscuous transcriptional activator because
it stimulates all classes of BHV-1 promoters (40, 65) and
non-BHV-1 promoters (Fig. 1). The ability of bICP0 to
interact with HDAC1 may play an important role in transcriptional
activation because HDACs, in general, are transcriptional repressors
that deacetylate histones and consequently convert chromatin into a
"closed conformation" (41, 59, 62). Our results
do not distinguish between bICP0 directly binding to HDAC1 or
to a complex containing HDAC1. Regardless of the mechanism, the
interaction between bICP0 and HDAC1 may (i) inhibit or alter
deacetylase activity, (ii) prevent interaction of HDAC1 with other
corepressors, (iii) prevent interaction of HDAC1 with DNA, or
(iv) alter the subcellular localization of HDAC1. The finding
that bICP0 expression correlated with reduced levels of
HDAC1 in crude cytoplasmic extracts prepared from BFL cells
suggested this was important in regulating the total HDAC1 activity.
Since bICP0 did not apparently reduce the levels of HDAC1 in
293 cells, we suggest that certain cell-type-specific factors play a
role in this process.
It is possible that bICP0 overrides or is dominant to the
repressor activity of HDAC1 and that the interaction between HDAC1 and
bICP0 is not required for relieving repression. However, four lines of evidence support the concept that an interaction between bICP0 and HDAC1 had an effect on transcriptional repression
induced by HDAC1. The first was that repression of the M4 promoter
construct by Mad was relieved by bICP0 or bICP0
(Fig. 3). The finding that bICP0 was unable to
trans-activate the minimal TK promoter (Fig. 2)
(35) but interacted with HDAC1 (Fig. 7) and relieved Mad induced repression of the M4 construct (Fig. 3) was the second line of
evidence. This finding argued against bICP0 merely
trans-activating the TK promoter in the M4 construct because
bICP0 was unable to trans-activate the minimal
TK promoter (pMinCAT) (Fig. 2C) (35). This study also
indicated that independent of the ability of bICP0 to
interact with HDAC1, the intact zinc ring finger provided a function
that was important for relieving Mad-induced repression. Since
bICP0 is localized within discrete domains of the nucleus of
infected (55) and transfected (35) cells, it
is possible that bICP0 can sequester HDAC1 to these domains.
The third line of evidence comes from its ability to relieve
HDAC1-mediated repression in quiescent cells (Fig. 5). The final line
of evidence was the finding that HDAC1 protein levels were reduced in
bovine cells transfected with bICP0.
In addition to histones, reversible acetylation regulates a growing
number of transcription factors, and thus HDACs are important for this
process. For example, E2F family members are differentially regulated
by acetylation (50) and acetylation of p53 represses its
transcriptional activity (36). E2F (29) and
p53 (12) are stimulated as a result of HSV-1 or BHV-1
infection, respectively, suggesting that these proteins are targets for
virus-induced changes in acetylation and deacytlation. A recent study
has demonstrated that the yeast HDAC1 interacts with two
G2/M checkpoint proteins (7), suggesting that
HDAC1 directly influences the cell cycle. This is an intriguing
observation because HSV-1-encoded ICP0 inhibits G2/M cell
cycle progression (47) and bICP0 inhibits the
growth and survival of transfected cells (35). Considering
that acetylation is thought to be as important as phosphorylation with
respect to posttranslationally modifying proteins (41), it
is not surprising that BHV-1 would target this pathway.
Cellular factors in actively growing cells can replace HSV-1-encoded
ICP0 (8), suggesting that factors in nondividing cells repress productive infection. HDAC1 repressed pM4minCAT promoter activity in growth-arrested, but not in actively growing, CV-1 cells
(Fig. 4), suggesting that an interaction between bICP0 and HDAC1 promotes viral gene expression in growth-restricted cells. This
hypothesis is supported by the finding that an HDAC inhibitor (trichostatin A) and ICP0 have similar effects on HSV-1 and cellular gene expression (30). With respect to reactivation from
latency, this may be particularly relevant because it is generally
accepted that ICP0 or, in the case of BHV-1, bICP0 triggers
reactivation (16). Since sensory neurons are terminally
differentiated cells and HSV-1 is organized as chromatin in latently
infected neurons (11), we hypothesize that HDAC1, in part,
maintains the genome in a "repressed transcriptional state". The
ability of bICP0 to interact with HDAC1 may be an important
step in relieving repression and inducing reactivation.
| |
ACKNOWLEDGMENTS |
This research was supported by grants from the USDA (9802064 and
2000-0206) and the Center for Biotechnology, UNL. Yange Zhang was
supported from funds derived from the Comparative Pathobiology Area of
Concentration and NIH (1P20RR15635).
We thank L. Kretzner for pM4minCAT and pMinCAT, D. Ayer for the Mad
plasmid, and T. Kouzarides for the HDAC1 plasmid.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Veterinary and Biomedical Sciences, Center for Biotechnology,
University of Nebraska, P.O. Box 830905, Lincoln, NE 68503-0905. Phone:
(402)-472-1890. Fax: (402)-472-9690. E-mail:
cjones{at}unlnotes.unl.edu.
| |
REFERENCES |
| 1.
|
Ayer, D. E., and R. N. Eisenman.
1993.
A switch from Myc:Max to Mad:Max heterocomplexes accompanies monocyte/macrophage differentiation.
Genes Dev.
7:2110-2119[Abstract/Free Full Text].
|
| 2.
|
Ayer, D. E.,
L. Kretzner, and R. N. Eisenman.
1993.
Mad: a heterodimeric partner for Max that antagonizes Myc transcriptional activity.
Cell
72:211-222[CrossRef][Medline].
|
| 3.
|
Baudino, T. A., and J. L. Cleveland.
2001.
The Max network gone mad.
Mol. Cell. Biol.
21:691-702[Free Full Text].
|
| 4.
|
Bowles, D. E.,
V. R. Holden,
Y. Zhao, and D. J. O'Callaghan.
1997.
The ICP0 protein of equine herpesvirus 1 is an early protein that independently transactivates expression of all classes of viral promoters.
J. Virol.
71:4904-4914[Abstract].
|
| 5.
|
Bowles, D. E.,
S. K. Kim, and D. J. O'Callaghan.
2000.
Characterization of the trans-activation properties of equine herpesvirus 1 EICP0 protein.
J. Virol.
74:1200-1208[Abstract/Free Full Text].
|
| 6.
|
Boyes, J.,
P. Byfield,
Y. Nakatani, and V. Ogryzko.
1998.
Regulation of activity of the transcription factor GATA-1 by acetylation.
Nature
396:594-598[CrossRef][Medline].
|
| 7.
|
Cai, R. L.,
Y. Yan-Neale,
M. A. Cueto,
H. Xu, and D. Cohen.
2000.
HDAC1, a histone deacetylase, forms a complex with Hus1 and Rad9, two G2/M checkpoint Rad proteins.
J. Biol. Chem.
275:27909-27916[Abstract/Free Full Text].
|
| 8.
|
Cai, W., and P. A. Schaffer.
1991.
A cellular function can enhance gene expression and plating efficiency of a mutant defective in the gene for ICP0, a transactivating protein of herpes simplex virus type 1.
J. Virol.
65:4078-4090[Abstract/Free Full Text].
|
| 9.
|
Chen, H.,
R. J. Lin,
W. Xie,
D. Wilpitz, and R. M. Evans.
1999.
Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase.
Cell
98:675-686[CrossRef][Medline].
|
| 10.
|
Coull, J. J.,
F. Romerio,
J. M. Sun,
J. L. Volker,
K. M. Galvin,
J. R. Davie,
Y. Shi,
U. Hansen, and D. M. Margolis.
2000.
The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1, J.
Virol.
74:6790-6799.
|
| 11.
|
Deshmane, S. L., and N. W. Fraser.
1989.
During latency, herpes simplex virus type 1 DNA is associated with nucleosomes in a chromatin structure.
J. Virol.
63:943-947[Abstract/Free Full Text].
|
| 12.
|
Devireddy, L. R., and C. J. Jones.
1999.
Activation of caspases and p53 by bovine herpesvirus 1 infection results in programmed cell death and efficient virus release.
J. Virol.
73:3778-3788[Abstract/Free Full Text].
|
| 13.
|
Doetzlhofer, A.,
H. Rotheneder,
G. Lagger,
M. Koranda,
V. Kurtev,
G. Brosch,
E. Wintersberger, and C. Seiser.
1999.
Histone deacetylase 1 can repress transcription by binding to Spl.
Mol. Cell. Biol.
19:5504-5511[Abstract/Free Full Text].
|
| 14.
|
Everett, R.,
P. O'Hare,
D. O'Rourke,
P. Barlow, and A. Orr.
1995.
Point mutations in the herpes simplex virus type 1 Vmw110 RING finger helix affect activation of gene expression, viral growth, and interaction with PML-containing nuclear structures.
J. Virol.
69:7339-7344[Abstract].
|
| 15.
|
Everett, R. D.
1988.
Analysis of the functional domains of herpes simplex virus type 1 immediate-early polypeptide Vmw110.
J. Mol. Biol.
202:87-96[CrossRef][Medline].
|
| 16.
|
Everett, R. D.
2000.
ICP0, a regulator of herpes simplex virus during lytic and latent infection.
Bioessays
22:761-770[CrossRef][Medline].
|
| 17.
|
Everett, R. D.,
P. Barlow,
A. Milner,
B. Luisi,
A. Orr,
G. Hope, and D. Lyon.
1993.
A novel arrangement of zinc-binding residues and secondary structure in the C3HC4 motif of an alpha herpes virus protein family.
J. Mol. Biol.
234:1038-1047[CrossRef][Medline].
|
| 18.
|
Everett, R. D.,
W. C. Earnshaw,
J. Findlay, and P. Lomonte.
1999.
Specific destruction of kinetochore protein CENP-C and disruption of cell division by herpes simplex virus immediate-early protein Vmw110.
EMBO J.
18:1526-1538[CrossRef][Medline].
|
| 19.
|
Everett, R. D.,
P. Lomonte,
T. Sternsdorf,
R. van Driel, and A. Orr.
1999.
Cell cycle regulation of PML modification and ND10 composition.
J. Cell Sci.
112:4581-4588[Abstract].
|
| 20.
|
Everett, R. D.,
M. Meredith,
A. Orr,
A. Cross,
M. Kathoria, and J. Parkinson.
1997.
A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein.
EMBO J.
16:1519-1530[CrossRef][Medline].
|
| 21.
|
Fischle, W.,
S. Emiliani,
M. J. Hendzel,
T. Nagase,
N. Nomura,
W. Voelter, and E. Verdin.
1999.
A new family of human histone deacetylases related to Saccharomyces cerevisiae HDA1p.
J. Biol. Chem.
274:11713-11720[Abstract/Free Full Text].
|
| 22.
|
Fraefel, C.,
J. Zeng,
Y. Choffat,
M. Engels,
M. Schwyzer, and M. Ackermann.
1994.
Identification and zinc dependence of the bovine herpesvirus 1 transactivator protein BICP0.
J. Virol.
68:3154-3162[Abstract/Free Full Text].
|
| 23.
|
Grozinger, C. M.,
C. A. Hassig, and S. L. Schreiber.
1999.
Three proteins define a class of human histone deacetylases related to yeast Hda1p.
Proc. Natl. Acad. Sci. USA
96:4868-4873[Abstract/Free Full Text].
|
| 24.
|
Grunstein, M.
1997.
Histone acetylation in chromatin structure and transcription.
Nature
389:349-352[CrossRef][Medline].
|
| 25.
|
Gu, W., and R. G. Roeder.
1997.
Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain.
Cell
90:595-606[CrossRef][Medline].
|
| 26.
|
Hanon, E.,
S. Hoornaert,
F. Dequiedt,
A. Vanderplasschen,
J. Lyaku,
L. Willems, and P. P. Pastoret.
1997.
Bovine herpesvirus 1-induced apoptosis occurs at the G0/G1 phase of the cell cycle.
Virology
232:351-358[CrossRef][Medline].
|
| 27.
|
Hassig, C. A.,
J. K. Tong,
T. C. Fleischer,
T. Owa,
P. G. Grable,
D. E. Ayer, and S. L. Schreiber.
1998.
A role for histone deacetylase activity in HDAC1-mediated transcriptional repression.
Proc. Natl. Acad. Sci. USA
95:3519-3524[Abstract/Free Full Text].
|
| 28.
|
Heinzel, T.,
R. M. Lavinsky,
T. M. Mullen,
M. Soderstrom,
C. D. Laherty,
J. Torchia,
W. M. Yang,
G. Brard,
S. D. Ngo,
J. R. Davie,
E. Seto,
R. N. Eisenman,
D. W. Rose,
C. K. Glass, and M. G. Rosenfeld.
1997.
A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression.
Nature
387:43-48[CrossRef][Medline].
|
| 29.
|
Hilton, M. J.,
D. Mounghane,
T. McLean,
N. V. Contractor,
J. O'Neil,
K. Carpenter, and S. L. Bachenheimer.
1995.
Induction by herpes simplex virus of free and heteromeric forms of E2F transcription factor.
Virology
213:624-638[CrossRef][Medline].
|
| 30.
|
Hobbs, W. E., Jr., and N. A. DeLuca.
1999.
Perturbation of cell cycle progression and cellular gene expression as a function of herpes simplex virus ICP0.
J. Virol.
73:8245-8255[Abstract/Free Full Text].
|
| 31.
|
Hossain, A.,
T. Holt,
J. Ciacci-Zanella, and C. Jones.
1997.
Analysis of cyclin-dependent kinase activity after herpes simplex virus type 2 infection.
J. Gen. Virol.
78:3341-3348[Abstract].
|
| 32.
|
Hurlin, P. J.,
D. E. Ayer,
C. Grandori, and R. N. Eisenman.
1994.
The Max transcription factor network: involvement of Mad in differentiation and an approach to identification of target genes.
Cold Spring Harbor Symp. Quant. Biol.
59:109-116[Abstract/Free Full Text].
|
| 33.
|
Hurlin, P. J.,
K. P. Foley,
D. E. Ayer,
R. N. Eisenman,
D. Hanahan, and J. M. Arbeit.
1995.
Regulation of Myc and Mad during epidermal differentiation and HPV-associated tumorigenesis.
Oncogene
11:2487-2501[Medline].
|
| 34.
|
Imhof, A.,
X. J. Yang,
V. V. Ogryzko,
Y. Nakatani,
A. P. Wolffe, and H. Ge.
1997.
Acetylation of general transcription factors by histone acetyltransferases.
Curr. Biol.
7:689-692[CrossRef][Medline].
|
| 35.
|
Inman, M.,
Y. Zhang,
V. Geiser, and C. Jones.
2001.
The zinc ring finger in the bICP0 protein encoded by bovine herpes virus-1 mediates toxicity and activates productive infection.
J. Gen. Virol.
82:483-492[Abstract/Free Full Text].
|
| 36.
|
Juan, L. J.,
W. J. Shia,
M. H. Chen,
W. M. Yang,
E. Seto,
Y. S. Lin, and C. W. Wu.
2000.
Histone deacetylases specifically down-regulate p53-dependent gene activation.
J. Biol. Chem.
275:20436-20443[Abstract/Free Full Text].
|
| 37.
|
Kawaguchi, Y.,
R. Bruni, and B. Roizman.
1997.
Interaction of herpes simplex virus 1 alpha regulatory protein ICP0 with elongation factor 1delta: ICP0 affects translational machinery.
J. Virol.
71:1019-1024[Abstract].
|
| 38.
|
Kawaguchi, Y.,
C. Van Sant, and B. Roizman.
1997.
Herpes simplex virus 1 alpha regulatory protein ICPO interacts with and stabilizes the cell cycle regulator cyclin D3.
J. Virol.
71:7328-7336[Abstract].
|
| 39.
|
Koppel, R.,
C. Fraefel,
B. Vogt,
L. J. Bello,
W. C. Lawrence, and M. Schwyzer.
1996.
Recombinant bovine herpesvirus-1 (BHV-1) lacking transactivator protein BICP0 entails lack of glycoprotein C and severely reduced infectivity.
Biol. Chem.
377:787-795.
|
| 40.
|
Koppel, R.,
B. Vogt, and M. Schwyzer.
1997.
Immediate-early protein BICP22 of bovine herpesvirus 1 trans-represses viral promoters of different kinetic classes and is itself regulated by BICP0 at transcriptional and posttranscriptional levels.
Arch. Virol.
142:2447-2464[CrossRef][Medline].
|
| 41.
|
Kouzarides, T.
2000.
Acetylation: a regulatory modification to rival phosphorylation?
EMBO J.
19:1176-1179[CrossRef][Medline].
|
| 42.
|
Kouzarides, T.
1999.
Histone acetylases and deacetylases in cell proliferation.
Curr. Opin. Genet. Dev.
9:40-48[CrossRef][Medline].
|
| 43.
|
Laherty, C. D.,
W. M. Yang,
J. M. Sun,
J. R. Davie,
E. Seto, and R. N. Eisenman.
1997.
Histone deacetylases associated with the mSin3 corepressor mediate Mad transcriptional repression.
Cell
89:349-356[CrossRef][Medline].
|
| 44.
|
Lees-Miller, S. P.,
M. C. Long,
M. A. Kilvert,
V. Lam,
S. A. Rice, and C. A. Spencer.
1996.
Attenuation of DNA-dependent protein kinase activity and its catalytic subunit by the herpes simplex virus type 1 transactivator ICP0.
J. Virol.
70:7471-7477[Abstract].
|
| 45.
|
Lium, E. K.,
C. A. Panagiotidis,
X. Wen, and S. J. Silverstein.
1998.
The NH2 terminus of the herpes simplex virus type 1 regulatory protein ICP0 contains a promoter-specific transcription activation domain.
J. Virol.
72:7785-7795[Abstract/Free Full Text].
|
| 46.
|
Lium, E. K., and S. Silverstein.
1997.
Mutational analysis of the herpes simplex virus type 1 ICP0 C3IIC4 zinc ring finger reveals a requirement for ICP0 in the expression of the essential alpha27 gene.
J. Virol.
71:8602-8614[Abstract].
|
| 47.
|
Lomonte, P., and R. D. Everett.
1999.
Herpes simplex virus type 1 immediate-early protein Vmw110 inhibits progression of cells through mitosis and from G1 into S phase of the cell cycle.
J. Virol.
73:9456-9467[Abstract/Free Full Text].
|
| 48.
|
Luo, R. X.,
A. A. Postigo, and D. C. Dean.
1998.
Rb interacts with histone deacetylase to repress transcription.
Cell
92:463-473[CrossRef][Medline].
|
| 49.
|
Magnaghi-Jaulin, L.,
R. Groisman,
I. Naguibneva,
P. Robin,
S. Lorain,
J. P. Le Villain,
F. Troalen,
D. Trouche, and A. Harel-Bellan.
1998.
Retinoblastoma protein represses transcription by recruiting a histone deacetylase.
Nature
391:601-605[CrossRef][Medline].
|
| 50.
|
Martinez-Balbas, M. A.,
U. M. Bauer,
S. J. Nielsen,
A. Brehm, and T. Kouzarides.
2000.
Regulation of E2F1 activity by acetylation.
EMBO J.
19:662-671[CrossRef][Medline].
|
| 51.
|
Maul, G. G., and R. D. Everett.
1994.
The nuclear location of PML, a cellular member of the C3HC4 zinc-binding domain protein family, is rearranged during herpes simplex virus infection by the C3HC4 viral protein ICP0.
J. Gen. Virol.
75:1223-1233[Abstract/Free Full Text].
|
| 52.
|
Maul, G. G.,
H. H. Guldner, and J. G. Spivack.
1993.
Modification of discrete nuclear domains induced by herpes simplex virus type 1 immediate early gene 1 product (ICP0).
J. Gen. Virol.
74:2679-2690[Abstract/Free Full Text].
|
| 53.
|
Miska, E. A.,
C. Karlsson,
E. Langley,
S. J. Nielsen,
J. Pines, and T. Kouzarides.
1999.
HDAC4 deacetylase associates with and represses the MEF2 transcription factor.
EMBO J.
18:5099-5107[CrossRef][Medline].
|
| 54.
|
Munshi, N.,
M. Merika,
J. Yie,
K. Senger,
G. Chen, and D. Thanos.
1998.
Acetylation of HMG I(Y) by CBP turns off IFN beta expression by disrupting the enhanceosome.
Mol. Cell.
2:457-467[CrossRef][Medline].
|
| 55.
|
Parkinson, J., and R. D. Everett.
2000.
Alphaherpesvirus proteins related to herpes simplex virus type 1 ICP0 affect cellular structures and proteins.
J. Virol.
74:10006-10017[Abstract/Free Full Text].
|
| 56.
|
Parkinson, J.,
S. P. Lees-Miller, and R. D. Everett.
1999.
Herpes simplex virus type 1 immediate-early protein vmw110 induces the proteasome-dependent degradation of the catalytic subunit of DNA-dependent protein kinase.
J. Virol.
73:650-657[Abstract/Free Full Text].
|
| 57.
|
Roussel, M. F.,
R. A. Ashmun,
C. J. Sherr,
R. N. Eisenman, and D. E. Ayer.
1996.
Inhibition of cell proliferation by the Mad1 transcriptional repressor.
Mol. Cell. Biol.
16:2796-2801[Abstract].
|
| 58.
|
Sakamuro, D., and G. C. Prendergast.
1999.
New Myc-interacting proteins: a second Myc network emerges.
Oncogene
18:2942-2954[CrossRef][Medline].
|
| 59.
|
Sterner, D. E., and S. L. Berger.
2000.
Acetylation of histones and transcription-related factors.
Microbiol. Mol. Biol. Rev.
64:435-459[Abstract/Free Full Text].
|
| 60.
|
Sterner, R.,
G. Vidali, and V. G. Allfrey.
1979.
Studies of acetylation and deacetylation in high mobility group proteins. Identification of the sites of acetylation in HMG-1.
J. Biol. Chem.
254:11577-11583[Free Full Text].
|
| 61.
|
Tikoo, S. K.,
M. Campos, and L. A. Babiuk.
1995.
Bovine herpesvirus 1 (BHV-1): biology, pathogenesis, and control.
Adv. Virus Res.
45:191-223[Medline].
|
| 62.
|
Tyler, J. K., and J. T. Kadonaga.
1999.
The "dark side" of chromatin remodeling: repressive effects on transcription.
Cell
99:443-446[CrossRef][Medline].
|
| 63.
|
Verdel, A., and S. Khochbin.
1999.
Identification of a new family of higher eukaryotic histone deacetylases. Coordinate expression of differentiation-dependent chromatin modifiers.
J. Biol. Chem.
274:2440-2445[Abstract/Free Full Text].
|
| 64.
|
Waltzer, L., and M. Bienz.
1998.
Drosophila CBP represses the transcription factor TCF to antagonize Wingless signalling.
Nature
395:521-525[CrossRef][Medline].
|
| 65.
|
Wirth, U. V.,
C. Fraefel,
B. Vogt,
C. Vlcek,
V. Paces, and M. Schwyzer.
1992.
Immediate-early RNA 2.9 and early RNA 2.6 of bovine herpesvirus 1 are 3' coterminal and encode a putative zinc finger transactivator protein.
J. Virol.
66:2763-2772[Abstract/Free Full Text].
|
| 66.
|
Wirth, U. V.,
B. Vogt, and M. Schwyzer.
1991.
The three major immediate-early transcripts of bovine herpesvirus 1 arise from two divergent and spliced transcription units.
J. Virol.
65:195-205[Abstract/Free Full Text].
|
| 67.
|
Zhang, W., and J. J. Bieker.
1998.
Acetylation and modulation of erythroid Kruppel-like factor (EKLF) activity by interaction with histone acetyltransferases.
Proc. Natl. Acad. Sci. USA
95:9855-9860[Abstract/Free Full Text].
|
| 68.
|
Zhang, Y.,
M. B. Dickman, and C. Jones.
1999.
The mycotoxin fumonisin B1 transcriptionally activates the p21 promoter through a cis-acting element containing two Sp1 binding sites.
J. Biol. Chem.
274:12367-12371[Abstract/Free Full Text].
|
Journal of Virology, October 2001, p. 9571-9578, Vol. 75, No. 20
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.20.9571-9578.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Saira, K., Zhou, Y., Jones, C.
(2007). The Infected Cell Protein 0 Encoded by Bovine Herpesvirus 1 (bICP0) Induces Degradation of Interferon Response Factor 3 and, Consequently, Inhibits Beta Interferon Promoter Activity. J. Virol.
81: 3077-3086
[Abstract]
[Full Text]
-
Katz, R. A., Jack-Scott, E., Narezkina, A., Palagin, I., Boimel, P., Kulkosky, J., Nicolas, E., Greger, J. G., Skalka, A. M.
(2007). High-Frequency Epigenetic Repression and Silencing of Retroviruses Can Be Antagonized by Histone Deacetylase Inhibitors and Transcriptional Activators, but Uniform Reactivation in Cell Clones Is Restricted by Additional Mechanisms. J. Virol.
81: 2592-2604
[Abstract]
[Full Text]
-
Thompson, R. L., Sawtell, N. M.
(2006). Evidence that the Herpes Simplex Virus Type 1 ICP0 Protein Does Not Initiate Reactivation from Latency In Vivo. J. Virol.
80: 10919-10930
[Abstract]
[Full Text]
-
Zhang, Y., Jiang, Y., Geiser, V., Zhou, J., Jones, C.
(2006). Bovine herpesvirus 1 immediate-early protein (bICP0) interacts with the histone acetyltransferase p300, which stimulates productive infection and gC promoter activity. J. Gen. Virol.
87: 1843-1851
[Abstract]
[Full Text]
-
Poon, A. P. W., Gu, H., Roizman, B.
(2006). ICP0 and the US3 protein kinase of herpes simplex virus 1 independently block histone deacetylation to enable gene expression. Proc. Natl. Acad. Sci. USA
103: 9993-9998
[Abstract]
[Full Text]
-
Henderson, G., Zhang, Y., Jones, C.
(2005). The bovine herpesvirus 1 gene encoding infected cell protein 0 (bICP0) can inhibit interferon-dependent transcription in the absence of other viral genes. J. Gen. Virol.
86: 2697-2702
[Abstract]
[Full Text]
-
Geiser, V., Zhang, Y., Jones, C.
(2005). Analysis of a bovine herpesvirus 1 recombinant virus that does not express the bICP0 protein. J. Gen. Virol.
86: 1987-1996
[Abstract]
[Full Text]
-
Zhang, Y., Zhou, J., Jones, C.
(2005). Identification of functional domains within the bICP0 protein encoded by bovine herpesvirus 1. J. Gen. Virol.
86: 879-886
[Abstract]
[Full Text]
-
Henderson, G., Zhang, Y., Inman, M., Jones, D., Jones, C.
(2004). Infected cell protein 0 encoded by bovine herpesvirus 1 can activate caspase 3 when overexpressed in transfected cells. J. Gen. Virol.
85: 3511-3516
[Abstract]
[Full Text]
-
Kent, J. R., Zeng, P.-Y., Atanasiu, D., Gardner, J., Fraser, N. W., Berger, S. L.
(2004). During Lytic Infection Herpes Simplex Virus Type 1 Is Associated with Histones Bearing Modifications That Correlate with Active Transcription. J. Virol.
78: 10178-10186
[Abstract]
[Full Text]
-
Lomonte, P., Thomas, J., Texier, P., Caron, C., Khochbin, S., Epstein, A. L.
(2004). Functional Interaction between Class II Histone Deacetylases and ICP0 of Herpes Simplex Virus Type 1. J. Virol.
78: 6744-6757
[Abstract]
[Full Text]
-
Saydam, O., Abril, C., Vogt, B., Ackermann, M., Schwyzer, M.
(2004). Transactivator Protein BICP0 of Bovine Herpesvirus 1 (BHV-1) Is Blocked by Prostaglandin D2 (PGD2), Which Points to a Mechanism for PGD2-Mediated Inhibition of BHV-1 Replication. J. Virol.
78: 3805-3810
[Abstract]
[Full Text]
-
Jiang, Y., Inman, M., Zhang, Y., Posadas, N. A., Jones, C.
(2004). A Mutation in the Latency-Related Gene of Bovine Herpesvirus 1 Inhibits Protein Expression from Open Reading Frame 2 and an Adjacent Reading Frame during Productive Infection. J. Virol.
78: 3184-3189
[Abstract]
[Full Text]
-
Poon, A. P. W., Liang, Y., Roizman, B.
(2003). Herpes Simplex Virus 1 Gene Expression Is Accelerated by Inhibitors of Histone Deacetylases in Rabbit Skin Cells Infected with a Mutant Carrying a cDNA Copy of the Infected-Cell Protein No. 0. J. Virol.
77: 12671-12678
[Abstract]
[Full Text]
-
Bianchi, E., Denti, S., Catena, R., Rossetti, G., Polo, S., Gasparian, S., Putignano, S., Rogge, L., Pardi, R.
(2003). Characterization of Human Constitutive Photomorphogenesis Protein 1, a RING Finger Ubiquitin Ligase That Interacts with Jun Transcription Factors and Modulates Their Transcriptional Activity. J. Biol. Chem.
278: 19682-19690
[Abstract]
[Full Text]
-
Geiser, V., Jones, C.
(2003). Stimulation of bovine herpesvirus-1 productive infection by the adenovirus E1A gene and a cell cycle regulatory gene, E2F-4. J. Gen. Virol.
84: 929-938
[Abstract]
[Full Text]
-
Geiser, V., Inman, M., Zhang, Y., Jones, C.
(2002). The latency-related gene of bovine herpesvirus-1 can inhibit the ability of bICP0 to activate productive infection. J. Gen. Virol.
83: 2965-2971
[Abstract]
[Full Text]
Top
Abstract
Introduction
