Department of Biological Sciences, Korea Advanced Institute
of Science and Technology, Taejeon 305-701, Korea
Kaposi's sarcoma-associated herpesvirus (KSHV) is a
gammaherpesvirus that has been implicated in the pathogenesis of
Kaposi's sarcoma. KSHV encodes K-bZIP (open reading frame K8), a
protein that belongs to the basic region-leucine zipper (bZIP) family of transcription factors. Here we show that K-bZIP associates with the
cellular transcription factor p53 directly in vitro and in vivo. This
interaction requires the bZIP domain of K-bZIP and the carboxy-terminal
region (amino acids 300 to 393) of p53. We also show that K-bZIP
represses the transcriptional activity of p53 which is required for
apoptosis of the host cell. These results imply that K-bZIP blocks
p53-mediated host cell death through its interaction with p53.
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TEXT |
Kaposi's sarcoma-associated
herpesvirus (KSHV; also designated human herpesvirus 8) has been
implicated as a major agent in the genesis of Kaposi's sarcoma and
several B-cell lymphoproliferative diseases (2, 3, 21).
Phylogenetic analysis of the KSHV genome sequence revealed that KSHV
belongs to the Gammaherpesvirinae subfamily; thus KSHV
shares significant sequence homology with herpesvirus saimiri and
Epstein-Barr virus (EBV) (22). The KSHV genome encodes a
basic region-leucine zipper (bZIP) protein called K-bZIP (open reading
frame K8), which forms a homodimer using its carboxyl-terminal bZIP
domain (17). The expression pattern of the K-bZIP gene
indicates that it is an early gene (30). The K-bZIP protein
typically localizes in the host cell nucleus (11).
Tetradecanoyl phorbol acetate (TPA) is reported to induce an authentic
lytic program and result in viral DNA replication and lytic gene
expression (25).
K-bZIP shows significant homology with EBV Zta (also designated EB1,
Zebra, and BZLF1) (5, 6, 10, 15, 17, 18). Zta is known to
play a crucial role in the initiation of the EBV lytic cascade, as
ectopic expression of Zta in latently infected cells is sufficient to
activate the entire EBV replicative cycle (4, 9). Zta is a
sequence-specific DNA binding protein that transactivates several EBV
early lytic promoters via canonical AP-1 binding sites or
Zta-responsive elements (6, 7, 12, 16, 31). In addition to
its role in vital transcription and replication, Zta was shown by Zhang
et al. (32) to interact directly with the tumor suppressor
and cell cycle regulatory protein p53 in vitro as well as in vivo and
to repress the ability of p53 to activate to transcription. Flemington
and colleagues (1, 26) showed that Zta caused cell cycle
arrest through the induction of cyclin-dependent kinase inhibitors p21
and p27. In this study, we show that K-bZIP associated directly with
p53 and determine the effects of K-bZIP binding on p53 function.
K-bZIP and p53 interact directly in vitro.
To determine
whether the K-bZIP and p53 proteins can interact directly in vitro, we
carried out glutathione S-transferase (GST) pull-down
assays. First, we cloned the full-length K-bZIP cDNA into various
expression vectors. The K-bZIP cDNA was synthesized using reverse
transcription-PCR and total RNA from BCBL-1 cells treated with TPA as
described previously (25). The PCR-amplified K-bZIP was
cleaved with EcoRI and XhoI and inserted
into pcDNA3 (Invitrogen, Groningen, The Netherlands), pGEX4T-1
(Amersham Pharmacia Biotech, Uppsala, Sweden), and pME18S
(FLAG-tagged SR
promoter plasmid [27]). The cloned
plasmids were designated pcDNA3/K-bZIP, pGEX4T-1/K-bZIP, and
FLAG-KbZIP, respectively. pGEX4T-1/K-bZIP was cleaved with
BamHI and NotI, inserted into pEBG, and
designated pEBG/K-bZIP. The splicing sites of K-bZIP cDNA were
confirmed by direct DNA sequencing. pcDNA3/K-bZIP was used for the in
vitro translation of K-bZIP. The cDNAs encoding various p53
subsequences were generated from full-length p53 cDNA (a gift from B. Vogelstein). PCR-amplified p53 cDNA was cleaved with BamHI
and XhoI and inserted into hemagglutinin (HA)-tagged pcDNA3
and designated HA-p53, and p53 cDNA was amplified by another primer
set, cleaved with EcoRI and XhoI, and designated
GST-p53. The p53 was expressed in bacteria as a GST fusion protein,
purified from bacterial cell extracts, and precipitated with in
vitro-translated K-bZIP using glutathione-Sepharose beads (Amersham
Pharmacia Biotech) as described previously (32). In
vitro-translated K-bZIP was retained by the GST-p53 fusion protein (as
compared with the GST control) (Fig. 1A).
Because the K-bZIP protein forms a homodimer (17), GST-KbZIP
served as a positive control to show that in vitro-translated K-bZIP was able to bind tightly to GST-KbZIP. In contrast, no detectable binding was observed with K-bZIP and the in vitro-translated luciferase control (Fig. 1B). These results show that K-bZIP interacts with p53
directly in vitro.
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FIG. 1.
K-bZIP interacts with p53 in vitro. Equal amounts of
GST, GST-p53, and GST-KbZIP were incubated with 35S-labeled
in vitro-translated K-bZIP (A) or luciferase (Luc) (B), and an aliquot
[Input (10%)] from each binding reaction was precipitated with
glutathione-Sepharose beads. The bead-bound proteins were eluted and
resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis
(SDS-PAGE). K-bZIP and Luc (both indicated by an arrow) were visualized
by autoradiography. GST-KbZIP was used as a positive control for K-bZIP
binding ability.
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K-bZIP and p53 proteins interact directly in vivo.
The
GST-KbZIP and HA-p53 expression plasmids (pEBG/K-bZIP and
pcDNA3/HA-p53, respectively) were cotransfected into 293T cells using
the calcium phosphate procedure (8). Forty-eight hours after
transfection, the cells were harvested and lysed to yield the cell
extract (14). GST-KbZIP was purified from the cell extract
using glutathione-Sepharose beads, and GST-KbZIP-bound HA-p53 was
detected by immunoblotting using a monoclonal antibody to HA. As shown
in Fig. 2A, GST-KbZIP bound to HA-p53
while GST alone did not. In the reverse experiment, Flag-KbZIP
(pME18S/KbZIP) and HA-p53 (pcDNA3/HA-p53) expression plasmids were
cotransfected into 293T cells and coimmunoprecipitation analyses were
performed as described previously (14). Incubation of the
transfected 293T cell extracts with a HA-specific antibody resulted in
the coimmunoprecipitation of HA-p53 and Flag-KbZIP (Fig. 2B).
Flag-KbZIP did not coimmunoprecipitate with HA alone. To confirm this
interaction in KSHV-infected cells, we performed the direct
coimmunoprecipitation assay for the KSHV-positive BCBL-1 cell line.
K-bZIP was expressed during the lytic replication and detected by
anti-KbZIP rabbit polyclonal antibody (Fig. 2C). Incubation of the cell
extract with a p53 specific antibody, DO-1 (Santa Cruz, Santa Cruz,
Calif.), resulted in the coimmunoprecipitation of p53 and K-bZIP (Fig. 2D, lane 4). However, K-bZIP was not detected either in KSHV-negative BJAB cell extract or in the immunoprecipitation with anti-HA antibody (Fig. 2D, lanes 3 and 5). These results demonstrate that K-bZIP interacts with p53 in vivo.
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FIG. 2.
K-bZIP interacts with p53 in vivo. (A) 293T cells
were transiently transfected with a plasmid encoding HA-p53
(pcDNA3/HA-p53) in combination with either GST (pEBG) (lanes labeled 1)
or GST-KbZIP (pEBG/K-bZIP) (lanes labeled 2). Whole-cell lysates were
prepared 48 h after transfection and were precipitated with
glutathione-Sepharose beads. The bead-bound proteins were separated on
a 7% polyacrylamide gel, transferred to a nitrocellulose membrane, and
immunoblotted (Western) with anti-HA antibody (upper panel) or anti-GST
antibody (lower panel). HA-p53 and GST-K-bZIP are indicated by arrows.
(B) 293T cells were transfected with a plasmid encoding FLAG-KbZIP
(pME18S/K-bZIP) in combination with either an HA-p53 expression plasmid
(pcDNA3/HA-p53) (lanes labeled 2) or a control plasmid (pcDNA3) (lanes
labeled 1). Cell lysates were subjected to immunoprecipitation (IP)
with anti-HA monoclonal antibody. Immunoprecipitated proteins were
separated on a 12% polyacrylamide gel, followed by immunoblotting
(Western) with anti-FLAG antibody (upper panel). Immunoglobulin G (IgG)
and Flag-K-bZIP are indicated by arrows. The identical membrane was
reprobed with anti-HA antibody (lower panel) to confirm the expression
of HA-p53 (indicated by an arrow). (C) The level of p53 and K-bZIP
during the lytic replication cycle. BCBL-1 cells were treated with TPA
as described previously (25). Whole cell lysates were
prepared after the indicated number of hours, and Western blots were
performed on equal quantities of whole cell extract (50 µg) by using
p53 specific monoclonal antibody (upper panel), K-bZIP specific
polyclonal antibody (middle panel), and  -actin antibody (lower
panel). (D) The direct coimmunoprecipitation assay was performed
using the BCBL-1 cell line 48 h after TPA induction. BCBL-1 cells
and BJAB cells (107 cells) were harvested, and cell lysates
were subjected to IP with p53 specific monoclonal antibody (lanes 3 and
4) and anti-HA antibody (lane 5). K-bZIP was detected using K-bZIP
polyclonal antibody (upper panel), and the same membrane was reprobed
with p53 antibody (bottom panel).
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p53-K-bZIP interaction required the carboxy-terminal region of p53
and the bZIP domain of K-bZIP.
To define the K-bZIP binding domain
within p53, in vitro-translated K-bZIP was incubated under the
appropriate binding conditions with a series of GST fusion proteins
that contained distinct domains of p53 (Fig. 3A and B). Although the
transactivation domain (amino acids 1 to 42) of p53 did not appear to
interact with K-bZIP, the p53 carboxy-terminal region (amino acids 300 to 393) interacted with K-bZIP. The p53 DNA binding domain (amino acids
100 to 300) also interacted with K-bZIP but binding was weaker than
with the p53 carboxy-terminal region (amino acids 300 to 393),
indicating that the carboxy-terminal region of p53 is the major binding
target of K-bZIP (Fig. 3B). The full-length GST-p53 fusion protein and GST protein were used as positive and negative controls, respectively.
To define the p53 binding domain within K-bZIP, experiments similar to
those described above were performed (Fig. 3C and
D). The most interesting structural
features of K-bZIP are the leucine zipper domain, which is involved in
homodimerization, and the adjunct basic region, which presumably
functions to bind DNA (17). Three GST-KbZIP fusion proteins
were synthesized: GST fused to K-bZIP with the leucine zipper deleted
(amino acids 1 to 189), GST fused to the bZIP domain (amino acids 122 to 237), and GST fused to the leucine zipper domain (amino acids 190 to
237). These GST fusion proteins were then used in GST pull-down
experiments with 35S-labeled, in vitro-translated p53. The
physical interaction between p53 and GST-KbZIP with the leucine zipper
domain deleted (amino acids 1 to 189) was so weak that in
vitro-translated p53 was barely detected. The interaction between p53
and the GST-bZIP domain (amino acids 122 to 237) fusion protein,
however, was similar to that between p53 and the wild-type K-bZIP, and
the GST-leucine zipper (amino acids 190 to 237) fusion did not interact
with p53. These results indicate that the leucine zipper domain is
essential but not sufficient for the interaction of K-bZIP with p53,
and the bZIP domain (amino acids 122 to 237) of K-bZIP, which comprises the putative DNA binding domain and leucine zipper domain, is sufficient for its binding to p53.
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FIG. 3.
Identification of domains involved in K-bZIP-p53
interaction. K-bZIP binds to the carboxy-terminal region of p53. (A)
Schematic representation of the domains of human p53. Numbers
correspond to the amino acid sequence. Indicated are the positions of
the transcriptional activation domain (TAD; amino acids 1 to 42), the
DNA binding domain (DBD; amino acids 100 to 300), and the
carboxy-terminal region (CT; amino acids 300 to 393). (B) Upper
panel, the p53 segments present in each of the GST fusion proteins used
in GST pull-down assays with 35S-labeled, in
vitro-translated K-bZIP. After subjecting the input (10%) and GST
pull-down reaction mixtures to SDS-PAGE, K-bZIP (indicated by arrow)
was visualized by autoradiography. Bottom panel, expression of GST-p53
fusion proteins. Purified GST fusion proteins of p53 deletion mutants
were electrophoresed on an SDS-13% polyacrylamide gel and visualized
by Coomassie brilliant blue staining. p53 associates with the bZIP
domain of K-bZIP. (C) Schematic representation of K-bZIP.
Indicated are the amino acid positions of the putative transcriptional
activation domain (TAD; amino acids 1 to 121), the putative DNA binding
domain (DBD; amino acids 122 to 189), and the leucine zipper domain
(ZIP; amino acids 190 to 237). (D) Upper panel, an experiment
similar to that described above for panel B performed using the
GST-KbZIP fusion proteins and 35S-labeled, in
vitro-translated p53 (indicated by an arrow). Bottom panel, expression
of GST-KbZIP fusion proteins. Purified GST fusion proteins of K-bZIP
deletion mutants were electrophoresed on an SDS-13% polyacrylamide
gel.
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Expression of K-bZIP in human cells represses the ability of p53 to
activate transcription.
The most notable biochemical property of
p53 is its DNA sequence-specific transcriptional activation of target
genes. In order to determine whether K-bZIP can influence p53 function,
a human cell line carrying a mutated p53 gene (C33A) was transiently
transfected (calcium phosphate method) with a luciferase reporter
plasmid that contained synthetic p53 response elements fused to the
luciferase gene (PG13-Luc) with or without HA-p53 (pcDNA3/HA-p53) along
with expression plasmid encoding wild-type FLAG-KbZIP (pME18S/K-bZIP). Twenty-four hours after transfection, the cells were rinsed with phosphate-buffered saline, resuspended in cell lysis buffer (Promega, Madison, Wis.), and incubated for 10 min on ice. Insoluble material was
removed by centrifugation, and luciferase activity in the cleared
supernatant was quantitated in the presence of luciferin (Promega) and
ATP using a luminometer (EG&G BERTHOLD, Pforzheim, Germany). Each assay
was normalized with total protein concentration in the samples. In the
presence of p53, transcription of the luciferase gene was induced up to
50-fold. However, in the presence of K-bZIP, p53-driven transcription
of the luciferase gene was reproducibly inhibited by 60% (Fig.
4A). Basal transcription was not
inhibited by K-bZIP, indicating that the transcriptional repression by
K-bZIP was not the result of general transcriptional repression.
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FIG. 4.
K-bZIP represses p53-dependent transcription in C33A
cells. (A) A synthetic p53 promoter fused to a luciferase reporter
gene (PG13-Luc) was repressed by K-bZIP. C33A cells, which carry a
mutated version of p53, were cotransfected with the reporter plasmid
PG13-Luc (0.5 µg) in the presence (+) or absence ( ) of the p53
expression plasmid pcDNA3/HA-p53 (0.5 µg) together with 2 to 4 µg
of the K-bZIP expression plasmid, FLAG-KbZIP (pME18S/K-bZIP). The total
amounts of transfected DNA (5 µg) in each dish were kept constant by
the addition of a blank plasmid (pME18S). Cell lysates were prepared 24 h after transfection, and luciferase activity was measured in the
lysates. Luciferase activity was normalized according to total protein
concentration in the sample. Transfections were performed in
triplicate, and the standard deviation is shown. (B) Repression of
a p53-dependent promoter by a series of K-bZIP mutants. C33A cells were
transfected with the PG13-Luc reporter plasmid (0.5 µg) with or
without pcDNA3/HA-p53 (0.5 µg), together with expression plasmids
encoding wild-type K-bZIP or one of three K-bZIP deletion mutants (4 µg). The total amount of transfected DNA in each dish was kept
constant by the addition of a blank plasmid (pME18S). Transfections
were performed in triplicate, and the standard deviation is shown.
(C) K-bZIP did not influence the unrelated activated
transcription. C33A cells were transfected with the Gal4-Luc reporter
plasmid (0.5 µg) with or without expression plasmids encoding
Gal4-VP16 (0.5 µg), together with K-bZIP expression plasmids.
Transfections were performed in triplicate, and the standard deviation
is shown. (D) The concentration of p53 and K-bZIP
protein-transfected C33A cells described above for panels A and B was
assessed by Western blot analysis (proteins are indicated by arrows).
Lane 1, 1 µg of PG13-Luc and 9 µg of blank plasmid (pME18S); lane
2, 1 µg of PG13-Luc, 1 µg of HA-p53 (pcDNA3/HA-p53), and 8 µg of
blank plasmid; lane 3, 1 µg of PG13-Luc, 8 µg of FLAG-KbZIP
(pME18S/K-bZIP), and 1 µg of blank plasmid; lane 4, 1 µg of
PG13-Luc, 1 µg of HA-p53, and 8 µg of FLAG-KbZIP; lane 5, 1 µg of
PG13-Luc, 1 µg of HA-p53, and 8 µg of FLAG-KbZIP lacking the
leucine zipper domain (1 to 189); lane 6, 1 µg of PG13-Luc, 1 µg of
HA-p53, and 8 µg of FLAG-KbZIP containing only the bZIP domain (122 to 237). HA-p53 protein was immunoprecipitated with anti-HA monoclonal
antibody and assessed by Western blotting with the same antibody. The
concentration of the various K-bZIP proteins in the cell lysates was
monitored by Western blotting using anti-FLAG monoclonal antibody.
Molecular sizes are shown at the left in kilodaltons.
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To characterize further the connection between K-bZIP-p53 interaction
and inhibition of p53 transcriptional activity, K-bZIP deletion mutants
(Fig. 3B) were used in transfection assays similar to those described
in Fig. 4A. In the presence of the K-bZIP mutant that lacked the
leucine zipper domain (amino acids 1 to 189), transcriptional
activation by p53 was inhibited to 20% (Fig. 4B). However, the K-bZIP
mutant that contained only the bZIP domain (amino acids 122 to 237)
inhibited p53-driven transcriptional activation to the same degree as
wild type. To show that K-bZIP did not influence the transcriptional
activity of an unrelated transactivator, we used Gal4-VP16 fusion
protein with Gal4-Luc. The promoter activated by Gal4-VP16 was not
influenced by K-bZIP (Fig. 4C). Expression of p53 and the K-bZIP
mutants in the transfected cells was monitored by Western blot assay,
which showed that the level of p53 and K-bZIP wild type and mutants did
not change significantly (Fig. 4D). These results indicate that the
repression of p53-driven transcriptional activity is related to the
physical interaction between p53 and K-bZIP.
Experiments described herein reveal that K-bZIP can interact directly
with p53 in vitro as well as in vivo. This interaction required the
bZIP domain of K-bZIP and the carboxy-terminal region of p53. The
expression of K-bZIP in transfected cells repressed the transcriptional
activity of p53. In addition, the ability of p53 to interact with the
various K-bZIP deletion mutant proteins correlated positively with
repression of p53-driven transcription of a reported gene. These
findings are consistent with the notion that the repression of
p53-driven transcription is caused by the functional association of p53
and K-bZIP.
The tumor suppressor protein p53 is a multifunctional transcriptional
regulatory protein that plays an important role in cell cycle arrest
and apoptosis (19). Various cellular and viral proteins have
been shown to inactivate p53 function via various cellular pathways
(19, 29). From our results, we hypothesized mechanisms by
which K-bZIP can impede p53 function. Because the carboxy-terminal
region of p53 associated with K-bZIP more tightly than did other p53
domains, we hypothesize that the carboxy-terminal region of p53 is the
main target of K-bZIP. The p53 carboxy-terminal region contains at
least three biological domains, nuclear localization, tetramerization,
and both nonspecific DNA binding and recognition of primary DNA damage
(28). It is well established that p53 forms tetramers
(13) via a tetramerization domain (amino acids 323 to 356)
in the carboxy-terminal region. p53 tetramerization appears to be
required for efficient transcriptional activation by p53 in vivo and
for p53-mediated suppression of the growth of carcinoma cell lines
(24). Consistent with our results, we propose a model
whereby K-bZIP blocks the tetramerization of p53 and, therefore,
inhibits p53 function. However, we cannot exclude the possibility that
K-bZIP may hinder the binding of p53 to DNA. This inhibition could
occur through the interaction of K-bZIP with the DNA binding domain of
p53, even though this interaction is weaker than the interaction of
K-bZIP with the tetramerization domain of p53.
p53 is known to be a regulator of cell growth, and the induction of p53
leads to either cell cycle arrest or apoptosis (19). As
K-bZIP is expressed during the lytic replication cycle, it does not
seem likely that K-bZIP is involved in the host cell proliferation
through blocking of p53-mediated cell cycle arrest. Instead, K-bZIP may
block host cell death mediated by p53 and help viral replication. It is
known that p53 mediates apoptosis using p53-dependent transcription,
such as bax and Fas/APO-1 (20, 23). Since K-bZIP inhibits
the transcriptional activity of p53, K-bZIP may block host cell death
mediated by p53. Further study is required to decipher K-bZIP's exact
role in KSHV viral replication.
This work was supported in part by grants from the National Research
Laboratory Program of the Korea Institute of Science and Technology
Evaluation and Planning (KISTEP), from the Korea Science and
Engineering Foundation (KOSEF) through the Protein Network Research
Center at Yonsei University, and from the BK21 Program from the
Ministry of Education, Korea.
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