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(Received for publication, September 26, 1996)
From the Division of Tumor Virology, Division of Neoplastic Disease
Mechanisms, Dana-Farber Cancer Institute, Harvard Medical School,
Boston, Massachusetts 02115
ABSTRACT The Epstein-Barr virus (EBV) immediate early
transactivator Zta is a basic leucine zipper (bZIP) transcription
factor that causes G0/G1 cell cycle arrest
through induction of the tumor suppressor protein, p53, and the
cyclin-dependent kinase inhibitors, p21 and p27 (Cayrol,
C., and Flemington, E. K. (1996) EMBO J. 15, 2748-2759).
Here, we report a genetic analysis of Zta-mediated G0/G1 growth arrest and p21 induction. The
majority of the Zta transactivation domain can be deleted (Z INTRODUCTION The Epstein-Barr virus (EBV)1 lytic
switch transactivator Zta (also referred to as BZLF1, EB1, and Zebra)
is a sequence-specific DNA-binding protein related to the bZIP family
of transcription factors, which plays a key role in the EBV replicative
cycle (1). By transactivating several early lytic cycle viral
promoters, Zta initiates the ordered cascade of EBV gene expression
that results in the induction of an estimated 100 or more viral
replication associated genes and culminates in virus production (2). In addition to its role in EBV lytic gene expression (3) and replication (4, 5), Zta can also regulate the expression of cellular factors such
as the growth suppressive cytokine transforming growth factor- Zta is a member of the bZIP family of transcription factors and binds
as a homodimer to multiple AP1 or ZRE
( We have recently demonstrated that Zta inhibits proliferation by
causing cell cycle arrest in G0/G1 in several
epithelial tumor cell lines (16). Zta-mediated
G0/G1 arrest was found to result from induction
of the tumor suppressor protein, p53, and the
cyclin-dependent kinase (CDK) inhibitors, p21/WAF-1/CIP-1 and p27/KIP-1, two pleiotropic mediators of cell cycle arrest, that
inhibit kinase activity of various cyclin-CDK complexes (17, 18, 19, 20, 21).
Inactivation of the retinoblastoma tumor suppressor protein (pRb), a
known target of cyclin-dependent kinases (22), was shown to
overcome Zta-mediated G0/G1 arrest, indicating that pRb or pRb-related proteins are involved in the pathway of growth
suppression induced by Zta (16).
Here we report on the ability of Zta mutants to cause
G0/G1 growth arrest and demonstrate that growth
arrest is independent of the transactivation function of Zta. These
results suggest a key role for the bZIP domain and flanking sequences
in Zta-mediated growth arrest and induction of p21.
EXPERIMENTAL PROCEDURES The pMARK vector encoding the cell
surface marker, CD7, was a generous gift from Seth Alper. pMARK-Zta
expression plasmids used in transient transfection assays were obtained
by subcloning the indicated Zta gene sequences into pMARK, downstream
from the SV40 promoter (9, 13, 16, 23).
Transient transfection
experiments using the human cervical carcinoma cell line, HeLa, were
performed employing the calcium phosphate precipitation procedure (24).
Cells were grown in high-glucose Dulbecco's modified Eagle's medium
(Cellgro), supplemented with 10% fetal bovine serum (Life
Technologies, Inc.), in a 5% CO2 environment. To analyze
the effects of Zta mutants on p21 expression, 106 cells
were transfected with 5 µg of pMARK control plasmid, 5 µg of
pMARK-Zta plasmid, or 5 µg of pMARK-Zta mutant expression vectors
(pMARK-Z The effects of Zta on
cell cycle distribution were determined as described previously (16).
Briefly, 1 × 106 HeLa cells were cotransfected with 5 µg of pMARK-Zta (or Zta mutants) plasmid encoding both the CD7 cell
surface marker and Zta together with 25 µg of pGL2 carrier plasmid,
using a standard calcium phosphate precipitation method (24). Control
experiments were performed using 5 µg of pMARK plasmid encoding only
CD7 marker and 25 µg of pGL2 carrier plasmid. Three days after
transfection, cells were collected, washed in PBS, and incubated with a
fluorescein isothiocyanate-conjugated CD7 monoclonal antibody (3A1,
diluted 1/10; Sigma) for 1 h on ice. Cells were
then washed in PBS, fixed with 70% cold ethanol for at least 30 min,
washed with PBS, treated for 30 min at 37 °C with RNase A (0.1 mg/ml), and stained with propidium iodide (69 µM)
(Sigma) in 38 mM sodium citrate. Cells were then analyzed by fluorescence-activated cell sorting (FACScan; Becton Dickinson) for both DNA content and CD7 staining. Analyses were
performed three times on 40,000 cells with similar results.
RESULTS To identify regions
of Zta that are important for its growth-inhibitory activity, a
transient transfection assay was employed (16). pMARK-Zta plasmids were
constructed that allow co-expression of Zta (or Zta mutants) and a
signal transduction-defective CD7 cell surface marker (25). HeLa cells
were transfected with pMARK-Zta, pMARK-Zta amino-terminal deletion
mutants, or the parental plasmid, pMARK. Three days after transfection,
the CD7 positive cell population was separated employing
fluorescence-activated cell sorting (FACS) and subjected to DNA content
analysis to assess the cell cycle distribution (Fig. 1).
A G0/G1 cell cycle arrest is observed in the
CD7+ population from pMARK-Zta transfected HeLa cells
(G0/G1: 88%; S: 5.7%) but not in the
CD7+ population of pMARK transfected HeLa cells
(G0/G1: 52.4%; S: 31%). Deletion of the
majority of the Zta activation domain (Z
To determine whether
the bZIP domain plays a role in growth inhibition, we tested two Zta
mutants with alterations in this domain, a Zta DNA-binding mutant
(Zdbm1), which has lost the ability to recognize ZRE (Zta-responsive
elements) sites (23) and a mutant with a two-amino acid substitution in
the Zta dimerization domain (Zdim), which is defective for dimerization
(9). The Zta DNA-binding mutant, Zdbm1, retains the capacity to block
cell cycle progression with an efficiency similar to that of wild type Zta since 86% of cells expressing Zdbm1 were found in the
G0/G1 population compared with 83% of cells
expressing wild type Zta (Fig. 2). This further suggests
that Zta-mediated G0/G1 growth arrest is
independent of its ability to transactivate AP1 or ZRE containing
cellular promoters. In contrast to Zdbm1, the dimerization mutant,
Zdim, has lost the ability to induce cell cycle arrest (only 55% of
cells in G0/G1), indicating that dimerization
and/or the integrity of the Zta coiled-coil dimerization structure is required for growth suppression (Fig. 2). Western blot analysis revealed that the expression level of the mutants which fail to induce
growth arrest (Zdim, Z
Our previous
studies demonstrated that Zta causes a p53-dependent
induction of p21 levels suggesting that this may be a key response
leading to cellular growth arrest (16). Based on this, the genetics of
Zta-mediated growth arrest might be expected to parallel the genetics
of p21 induction. As shown in Fig. 3, p21 is induced by
Zta, Z
DISCUSSION Several conclusions can be derived from this limited genetic
analysis. First, a tight correlation exists between growth arrest and
induction of p21. We showed previously that induction of p21 by Zta is
mediated through p53 (16), and, indeed, induction of p53 follows the
same genetics as that of p21 (data not shown). Therefore, this pathway
is likely to play an important role in transmitting Zta growth arrest
signals.
These studies also demonstrate that a carboxyl-terminal region of Zta
encompassing the bZIP domain is sufficient to cause a
G0/G1 growth arrest. Deletion of the
amino-terminal half of Zta does not significantly affect its capacity
to block G1/S progression since the mutant, Z The ability of the Zta DNA-binding mutant, Zdbm1, to efficiently induce
cellular growth arrest provides additional support for the idea that
the transactivation function of Zta is not required for inducing growth
arrest. We have previously reported that Zta DNA binding mutants,
including Zdbm1, can activate certain promoters in transient reporter
assays probably through protein-protein interactions (23). However, in
these studies, we found that Zdbm1 and wild type Zta elicited
transcriptional activation through distinct promoter elements and they
may therefore have distinct promoter specificities. Although we cannot
rule out the possibility that transcriptional activation plays a role
in eliciting cellular growth arrest, we favor a model whereby Zta
induces growth arrest through protein-protein interactions with key
cell cycle control proteins. Previous studies demonstrated an
interaction between p53 and the dimerization domain of Zta (26).
Moreover, in this study, it was suggested that the Zta-mediated
post-transcriptional induction of p53 might arise through masking of
p53 sequences involved in targeting it for
ubiquitin-dependent degradation (26). Since the results
presented here point to a critical role for Zta's bZIP domain in
eliciting G0/G1 growth arrest and p21
induction, this is a reasonable possibility.
Results presented here suggest that sequences upstream from the bZIP
domain, amino acids 128 to 167, are also required for p21 induction and
for cellular growth arrest. At this time we don't know whether this
sequence might contribute to or stabilize interactions with key
cellular proteins or whether this region provides conformational
contributions to the bZIP structure.
The finding that the carboxyl-terminal region of Zta encompassing the
bZIP domain is sufficient to block cell proliferation further
emphasizes the critical role of bZIP domains and bZIP transcription
factors in the control of cell proliferation. Other bZIP factors have
previously been implicated in affecting cell growth control pathways.
For example, the AP1 family bZIP factors, c-Fos and c-Jun, promote cell
proliferation in some settings and are associated with differentiation
in several cellular differentiation model systems (27, 28, 29, 30, 31). The
Caenorhabditis elegans bZIP protein Ces-2 has been shown to
induce programmed cell death (32). Further investigations into
mechanisms driving Zta-mediated G0/G1 growth
arrest should reveal additional insights into the role of bZIP
transcription factors in cell proliferation.
FOOTNOTES Acknowledgments We would like to thank Seth Alper for kindly
providing pMARK-CD7 expression plasmid. We are grateful to Dr. Antonio
Rodriguez for his help and discussions. We are also grateful to Jack
Strominger for continuing encouragement and support.
REFERENCES
Volume 271, Number 50,
Issue of December 13, 1996
pp. 31799-31802
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
COMMUNICATION:
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
FOOTNOTES
Acknowledgments
REFERENCES
1-128)
without significantly affecting the ability of Zta to elicit growth
arrest. A larger amino-terminal deletion (Z1-167) abrogates the
ability of Zta to inhibit proliferation, mapping the growth-inhibitory
domain to a carboxyl-terminal region encompassing the bZIP domain
(amino acids 128-245). The integrity of the bZIP domain is required
for growth suppression since a two-amino acid mutant which is defective for homodimerization, fails to induce cell cycle arrest. Western blot
analysis of p21 expression in cells expressing Zta mutants reveals that
the ability of Zta mutants to cause G0/G1
growth arrest is intimately related to their capacity to induce p21
expression. Together, these data demonstrate that a carboxyl-terminal
region of Zta that includes the bZIP domain is sufficient to mediate G0/G1 growth arrest and p21 induction.
(6).
ta-
esponsive 
lements) sites in
the promoters of target genes (7). The carboxyl-terminal bZIP domain of
Zta has significant amino acid homology with the basic DNA-binding and
dimerization domains of c-Fos (7) and C/EBP (8). The bZIP domain of Zta
mediates homodimerization through a coiled-coil interaction, although
Zta lacks the heptad repeat of leucine residues found in the leucine
zipper proteins (8, 9, 10). The amino-terminal region of Zta does not appear to influence dimerization or DNA binding, but plays a role in
activation of transcription (11, 12, 13). The Zta activation domain has
been shown to mediate association with the general transcription factor
TFIIA (14, 15) and the TATA box-binding protein TBP (12). Amino acids
between 25 and 86 were shown to be critical for this latter interaction
(12).
1-128, pMARK-Z1-167, pMARK-Zdbm1, pMARK-Zdim). Cells
were harvested 72 h following transfection, and extracts were
assayed for p21 expression by Western blot analysis with a mouse
monoclonal antibody against p21 (sc-187, Santa-Cruz Biotechnology), as
described previously (16).
1-128) does not
significantly affect the ability of Zta to elicit a
G0/G1 growth arrest since only 3.9% of cells
expressing Z1-128 were in S phase compared with 31% in control
cells transfected with pMARK. This amino-terminal truncation severely
impairs the ability of Zta to induce transcriptional activation ((13)
and data not shown) and deletes the region shown previously to mediate
association with the TATA box-binding protein TBP (12). Therefore,
Zta-mediated growth arrest is likely independent of its ability to
activate transcription or to interact with TBP. To further refine the
analysis of Zta sequences involved in mediating growth arrest, a mutant with a larger amino-terminal deletion was tested (Fig. 1). Deletion of
the first 167 amino acids (Z1-167) abrogated the ability of Zta to
cause growth arrest, indicating that key Zta growth-inhibitory sequences are located in a carboxyl-terminal region of Zta (amino acids
128-245). Essentially identical results were obtained when these
constructs (Zwt, Z1-128, Z1-167) were expressed in the EBV-negative nasopharyngeal cell line, AdAH, and the EBV-positive nasopharyngeal cell line, NPC-KT, two other epithelial cell lines sensitive to the growth-inhibitory effects of Zta ((16) and data not
shown).
Fig. 1.
The amino terminus of Zta is not required for
Zta-induced G0/G1 growth arrest. Zta
amino-terminal deletion mutants were analyzed for their ability to
inhibit the growth of HeLa cells. Cells were transiently transfected
with 5 µg of pMARK (control encoding only cell surface CD7 marker)
pMARK-Zta (encoding both CD7 marker and Zta), or pMARK-Zta deletion
mutants vectors, pMARK-Z1-128 and pMARK-Z1-167 (encoding both
CD7 marker and Zta mutants). Cell cycle distribution was determined on
transfected cells (CD7+) by FACS. The experiment shown here
is representative of three experiments.
[View Larger Version of this Image (21K GIF file)]
1-167) is similar to that of mutants that
block cell cycle progression (data not shown). In addition, all mutants
are localized to the nucleus as judged by immunofluorescence analysis
(data not shown). Together, these data demonstrate that Zta-induced
growth arrest is mediated by a carboxyl-terminal region and requires an
intact bZIP domain.
Fig. 2.
A two-amino acid substitution in the bZIP
domain abolishes Zta-mediated G0/G1 growth
arrest. Zta mutants in the bZIP domain were analyzed for their
ability to inhibit the growth of HeLa cells. Cells were transiently
transfected with 5 µg of pMARK (encoding only cell surface CD7
marker), pMARK-Zta, pMARK-Zdbm1 (DNA binding mutant), or pMARK-Zdim
(dimerization mutant 214s-218s). Cell cycle distribution was determined
on transfected cells (CD7+) by FACS. The experiment shown
here is representative of three experiments.
[View Larger Version of this Image (21K GIF file)]
1-128, and Zdbm1 but not Z1-167 or Zdim. Therefore, a
tight correlation exists between the ability of Zta mutants to elicit a
G0/G1 growth arrest and to induce p21
expression.
Fig. 3.
Western blot analysis of p21 expression in
cells transfected with Zta mutant expression vectors. Whole cell
extracts from cells transfected with pMARK, pMARK-Zta, or pMARK-Z
mutants expression vectors (pMARK-Z1-128, pMARK-Z1-167,
pMARK-Zdbm1, pMARK-Zdim) were used for immunodetection of p21, using
the monoclonal antibody sc-187.
[View Larger Version of this Image (60K GIF file)]
1-128,
inhibited the percentage of cells in S phase, as efficiently as wild
type Zta (respectively 3.9% and 5.7% versus 31% in
untransfected cells). We note, however, that the G2/M
population is not reduced in Z1-128 expressing cells indicating an
inability of cells to traverse through G2/M. This suggests
that sequences between amino acids 1 and 128 are required for
progression through the G2/M checkpoint in the context of other Zta-mediated alterations in cellular growth control pathways. This apparent G2/M arrest is not evident in
Zdbm1-transfected cells indicating that the inability of Z1-128 to
transactivate ZRE containing cellular promoters is not the sole defect
leading to a block in G2/M progression. Instead, it is
possible that these sequences contribute to some functional
interactions with factors involved in controlling the G2/M
checkpoint control.
¶
Present address: Institut de Pharmacologie et de Biologie
Structurale du CNRS, 205, Route de Narbonne, 31077 Toulouse,
France.
To whom correspondence should be addressed: Dana-Farber Cancer
Institute, Division of Tumor Virology, Mayer 613, 44 Binney St.,
Boston, MA 02115. Tel.: 617-632-3852; Fax: 617-632-2662; E-mail:
erik_flemington{at}macmailgw.dfci.harvard.edu.
1
The abbreviations used are: EBV, Epstein-Barr
virus; bZIP, basic leucine zipper; TBP, TATA box-binding protein; CDK,
cyclin-dependent kinase; Rb, retinoblastoma protein; ZRE,
Zta-responsive elements; PBS, phosphate-buffered saline; FACS,
fluorescence-activated cell sorting.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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