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Departments of Obstetrics and Gynecology [T. K., S. K., M. T., M. I.] and Urology [Y. K.], School of Medicine, Kanazawa University, Ishikawa 920, Japan, and Departments of Obstetrics and Gynecology [K. H.] and Neurosurgery [H. H.], School of Medicine, Ehime University, Ehime 791-0204, Japan
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ABSTRACT |
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Introduction |
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A number of studies using newly developed telomeric repeat amplification protocol assays have demonstrated that telomerase activity is observed in most malignant tumors but is usually repressed in normal somatic tissues, suggesting that telomerase activation may be a critical step in cellular immortality and carcinogenesis (5 , 6) . However, subsequent studies have revealed that telomerase is activated not only in tumors but also in some types of normal somatic cells, such as hematopoietic stem cells, keratinocytes in basal layers of the epidermis, and uterine endometrial cells, all of which have high regenerative and proliferative capacity (7, 8, 9) , and that telomerase activity is up-regulated on cell proliferation and cell cycle exit into G0 or cell differentiation accompanies down-regulation of telomerase activity (10, 11, 12) . These findings suggest that the factors that regulate the cell cycle may play roles in telomerase regulation. However, little information on such factors has been obtained.
Recent studies have identified three major subunits comprising the human telomerase complex. The RNA component of human telomerase (hTR2 ) provides the template for telomere repeat synthesis (13) . Telomerase-associated protein (TP1) has also been cloned as a component of telomerase, but its function remains unclear (14 , 15) . The most important component responsible for the enzymatic activity of telomerase is hTERT (16 , 17) . Studies have found that hTERT is expressed in most malignant tumors but not in normal tissues, and the expression of hTERT is closely associated with telomerase activity, whereas two other factors are constitutively expressed in both tumors and normal tissues and are not directly associated with the enzymatic activity of telomerase (18, 19, 20) . Introduction of hTERT cDNA into normal cells confers telomerase activity in these cells (21 , 22) . hTERT-expressing normal cell clones have an extended life span without any change in karyotype (23) . These findings suggest that hTERT is a critical determinant of telomerase activity.
Recently, abrogation of p53 function by the introduction of mutant p53 has been reported to induce cellular immortality and telomerase reactivation in mammary epithelial cells (24) . It has also been reported that HPV-16 oncoprotein E6, which is known to bind p53 and to promote its degradation, up-regulates telomerase activity (25 , 26) . These findings suggest the possible involvement of p53 in telomerase regulation. In the present study, we use adenovirus-mediated gene transfer to examine the effect of p53 on telomerase activity in cervical cancer cells.
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Materials and Methods |
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Recombinant Adenovirus and Infection.
The recombinant p53 adenoviral vector Ad5CMV-p53
contains the cytomegalovirus promoter, wild-type p53 cDNA, and a SV40
polyadenylation signal in a minigene cassette inserted into the
E1-deleted region of modified adenovirus Ad5 (27)
. The
adenovirus containing the ß-gal gene, AdCMV-LacZ, was used
to determine transduction efficiencies or was used as a control. Viral
stocks were propagated in 293 cells, which were derived from primary
embryonal kidney cells transformed by introducing sheared fragments of
Ad5 DNA. This cell line contains E1 and is thus highly permissive of
the replication of the E1 replication-deficient adenovirus. Virus was
purified from this cell to obtain viral stock. Cells were harvested at
various time points after infection, pelleted, resuspended in PBS, and
lysed by three cycles of freezing and thawing. Cell debris was removed
by subjecting the lysed cells to CsCl gradient centrifugation.
Concentrated virus was dialyzed and stored at -80°C. Infection was
carried out by adding the virus to high-glucose DMEM and to the cell
monolayers. The cells were incubated at 37°C for 60 min with constant
agitation. Medium was added, and the cells were incubated at 37°C for
the desired length of time. The viral titers were determined by plaque
assays.
Stretch PCR Assay.
For quantitative analysis of telomerase activity, stretch PCR assays
were performed using the Telochaser system according to the
manufacturer’s protocol (Toyobo, Tokyo, Japan). The PCR products were
electrophoresed on a 7% polyacrylamide gel and visualized with SYBR
Green I Nucleic Acid Gel Stain (FMC BioProducts, Rockland, ME). The
band intensity of the telomerase ladders was analyzed by NIH Image
picture analyzing software.
RNA-PCR Analysis.
Analysis of Bcl-2 mRNA expression was performed by RT-PCR amplification
using the primer pair 5'-ACTTGTGGCCCAGATAGGCACCCAG-3' (forward primer)
and 5'-CGACTTCGCCGAGATGTCCAGCCAG-3' (reverse primer) as described
previously (28)
. hTERT mRNA was amplified using the primer
pair 5'-CGGAAGAGTGTCTGGAGCAA-3' (LT5) and
5'-GGATGAAGCGGAGTCTGGA-3'(LT6; Ref. 17
). hTR was amplified
using the primer pair 5'-TCTAACCCTAACTGAGAAGGGCGTAG-3' (F3b) and
5'-GTTTGCTCTAGAATGAACGGTGGAAG-3' (R3c; Ref. 17
).
Total RNA was isolated from the tissues using Isogen (Nippon Gene,
Tokyo, Japan) according to the manufacturer’s protocol. cDNA
was synthesized from 1 µg of RNA using the RNA PCR kit version 2
(TaKaRa, Otsu, Japan) with random primers. To amplify the cDNA, 2-µl
aliquots of the reverse-transcribed cDNA were subjected to 28 cycles of
PCR in 50 µl of 1x buffer [10 mM Tris-HCl (pH 8.3), 2.5
mM MgCl2, and 50 mM KCl]
containing 200 µM each of dATP, dCTP, dGTP, and dTTP; 2.5
units of Taq DNA polymerase (TaKaRa); and 0.2 µM of
specific primers. Each cycle consisted of denaturation at 94°C for
30 s, annealing at 60°C for 30 s, and extension at 72°C
for 90 s. PCR products were electrophoresed in 7% polyacrylamide
gel and stained with SYBR green (FMC BioProducts). The efficiency of
cDNA synthesis from each sample was estimated by PCR with
glyceraldehyde-3-phosphate dehydrogenase-specific primers as described
previously (17)
.
Plasmid Construction.
The structures of hTERT promoter-LUC plasmids are shown in Fig. 4A.
Various lengths of DNA fragments upstream of the
initiating ATG codon of the hTERT gene were PCR-amplified and inserted
into LUC reporter vector pGL3-Basic, a promoterless and enhancerless
vector (Promega, Madison, WI), in a sense orientation relative to the
LUC coding sequence at the Mlu1 and BglII sites.
A mutant reporter plasmid (pGL3–181Sp1 MT) containing mutations in
five Sp1 binding sites at -109, -88, -56, -36, and -7 was prepared
using PCR-based site-specific mutagenesis. As a positive control
plasmid, pGL3-Control (Promega) was used, in which the LUC gene is
driven by the SV40 LT enhancer/promoter. The names of reporter
constructs with serial deletions of the 3.3 kb of hTERT promoter were
assigned according to the 5'-end nucleotide numbers of inserted
promoter sequences (29)
. p53 expression vector (pC53-SN3)
was kindly provided by Dr. Bert Vogelstein (30)
.
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Results |
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there was a linear
correlation between the number of infected cells and the number of
adenovirus particles used for infection. The cells inoculated with a
single dose of Ad5CMV-LacZ at a MOI of 12.5 or greater
exhibited almost 100% blue-stained cells.
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especially at a MOI of 25 or greater. Samples isolated
from noninfected SiHa cells exhibited very low levels of p53 protein.
The time course of p53 expression in SiHa cells is shown in Fig. 1C.
Cell extracts were prepared at various time points after
infection. p53 protein expression peaked 3 days after infection and
declined thereafter, but detectable expression was observed even at day
7.
Overexpression of p53 Represses Telomerase Activity with
Down-Regulation of hTERT.
To examine the effects of p53 overexpression on telomerase activity,
SiHa cells were infected with Ad5CMV-LacZ or
Ad5CMV-p53 at various MOIs, and cell extracts were isolated
72 h after infection and examined for telomerase activity by the
quantitative stretch PCR assay. As shown in Fig. 2A,
infection by
Ad5CMV-p53 decreased telomerase activity at a MOI of 25 and
significantly eliminated it at a MOI of 50, whereas infection by
Ad5CMV-LacZ had no effect on telomerase activity. Time
course experiments were also performed in which repression of
telomerase activity became obvious 48 h after infection, and
complete loss of telomerase activity was observed 72 h after
infection (Fig. 2B).
In contrast, no significant change in
telomerase activity was detected in cells infected with
Ad5CMV-LacZ as negative controls. We extended analyses on
the onset of telomerase repression, monitoring telomerase activity
every 6 h, and we found that repression occurred 36 h after
the infection (Fig. 2C).
Expression of hTERT and hTR was
next examined by RT-PCR analyses. A significant decrease in hTERT mRNA
expression was observed 12 h after infection with
Ad5CMV-p53, whereas expression of hTR was not altered during
the time course of observation (Fig. 2D).
Thus,
overexpression of p53 down-regulated hTERT mRNA expression, followed by
telomerase repression. A recent study reported that antiapoptotic
factor Bcl-2 activates telomerase (32)
. Because the
expression of Bcl-2 is known to be regulated by p53 in some cell types
(33)
, the change in Bcl-2 expression after infection by
Ad5CMV-p53 was examined by RT-PCR analyses, but no
significant change in expression was detected during the time course of
observation, suggesting that deregulation of Bcl-2 is not involved in
telomerase repression by p53.
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When cells infected with Ad5CMV-p53 were
fixed and subjected to a terminal deoxynucleotidyl transferase-mediated
nick end labeling assay, no increase in stained cells was detected
after infection (data not shown). Taken together, these findings
indicate that overexpression of p53 in SiHa cells represses telomerase
without altering cellular growth properties or inducing apoptosis.
p53 Represses Transcriptional Activity of hTERT
Promoter.
The finding that p53 down-regulates hTERT mRNA suggests that
hTERT expression is controlled by p53 at the transcriptional level. In
a previous study, we cloned 3.3 kb of the 5'-flanking sequences of the
hTERT gene (29)
. A computer-asisted homology search
revealed two potential p53 binding motifs at -1877 (AGGCTGGTCT) and
-1240 (AGGCCTGTTC) in the 5'-flanking sequences (Fig. 4A).
To examine whether p53
regulates the promoter activity of hTERT, LUC assays were
performed using SiHa cells in which p53 expression vectors were
cotransfected with 3.3 kb hTERT-promoter LUC reporters (pGL3–3328). As
a result, overexpression of p53 significantly repressed the promoter
activity of hTERT (Fig. 4B).
Similar inhibition of
telomerase activity was observed for other types of cells, such as
ME180 and Ishikawa cells (derived from uterine cancers) as well as
DU145 and TSU-PR1 cells (derived from prostate cancers).
The Proximal Core Promoter of the hTERT Gene that Binds Cellular
Factor Sp1 Is Responsible for p53-mediated Transcriptional Repression.
To identify the elements responsible for the down-regulation of
hTERT, serial deletion mutants of reporter plasmids were
prepared (Fig. 4A),
and LUC assays were performed. p53
overexpression repressed transcriptional activity not only in wild-type
pGL3–3328 but also in its deletion mutants (Fig. 4C).
Interestingly, transcriptional activity in pGL3–1375 and pGL3–1175,
which lack one or two potential p53 binding motifs, respectively, was
also repressed by p53 overexpression. Repression was further observed
in mutants with more extended deletions, and the proximal 181-bp region
(pGL3–181) could respond to p53 overexpression. Our previous study
demonstrated that this region functions as a core promoter essential
for transactivation of hTERT in cancer cells (29)
. This
core promoter contains five GC-boxes and an E-box that bind
transcription factor Sp1 and Myc/Max, respectively (Ref.
29
; Fig. 4A).
Myc proteins have been found to
be critical factors for activation of hTERT transcription (34
, 35)
. However, deletion of the E-box (pGL3–150) did not affect
the repressive effect of p53, indicating that the remaining 150-bp
region containing five GC-boxes was responsible for this repression.
Interestingly, even the proximal 32-bp region (pGL3–32) containing one
Sp1 site responded to p53 overexpression. In contrast, p53
overexpression failed to repress transcription of mutant p-181
(pGL3–181Sp1 MT), in which all Sp1 sites had been eliminated by
substitution mutations.
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Discussion |
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Telomerase is known to be a regulated enzyme, and its activity is critically controlled in association with cell proliferation. p53 is a cell cycle regulator and induces G1 arrest of the cell cycle by activating p21 transcription on DNA damage signals (36) . It also induces apoptosis through transcriptional activation of Bax or p53-induced genes (37 , 38) . We therefore examined whether telomerase repression was due to growth inhibition or apoptosis induced by p53. However, under our assay conditions, no significant growth inhibition or apoptosis was observed until 42 h after introduction of the p53 gene. These findings suggest that repression of telomerase activity is not simply an effect of growth inhibition or apoptosis of the cells.
Telomerase repression was observed 24 h after down-regulation of
hTERT mRNA expression. This is consistent with the observation that the
half-life of hTERT is approximately 24 h (12)
and
suggests that telomerase repression is achieved at the transcriptional
level of hTERT. The early onset of hTERT down-regulation (12 h after
infection) indicates that p53 directly regulates hTERT transcription.
We have, in fact, identified putative p53 binding motifs in the hTERT
promoter. Transient expression assays using hTERT promoter-reporter
plasmids demonstrated that p53 significantly represses the
transcriptional activity of hTERT. However, these motifs did not play
causative roles in this down-regulation. Serial deletion assays
revealed that the 181-bp core promoter region that contains an E-box
and five GC-boxes responded to p53 overexpression. However, deletion of
the E-box did not alter the effect of p53, indicating that the
remaining 150-bp region containing five Sp1 sites was responsible for
transcriptional repression. Interestingly, even the 32-bp minimal
promoter region containing one Sp1 site could respond to p53
overexpression. Abrogation of Sp1 bindings by substitution mutations
(pGL3–181Sp1 MT) resulted in a marked loss of transcriptional activity
(Fig. 4C),
indicating that Sp1 is a critical transactivator
possibly involved in the basal transcription of hTERT. Interestingly,
p53 overexpression failed to repress transcription of pGL3–181Sp1 MT.
These findings suggest that Sp1 plays a role in p53-mediated
transcriptional repression. Recent studies have demonstrated that p53
negatively regulates gene transcription from GC-rich promoters
containing SP1 binding sites, such as the insulin-like growth factor I
receptor gene (39)
. This negative regulation is performed
via protein-protein interaction of p53 with Sp1. Although such an
interaction was not confirmed in this study, it might be one of the
mechanisms by which p53 represses hTERT transcription.
Interaction of p53 with transcriptional coactivator p300 has recently
been demonstrated. p300 is known to bind specific transcription factors
such as the cAMP-responsive element-binding protein, the Stat
family, c-Myc, c-jun, and nuclear factor 
B, all of which are
essential transactivators for various genes, through protein-protein
interaction (reviewed in Ref. 40
). p300 also binds to
basal transcription factors such as transcription factor IID. Thus,
p300 functions as a bridging factor that connects enhancer-binding
proteins with basal transcription factors to facilitate transcription
of target genes (40)
. It has been suggested that p300 is a
limited cellular factor and that overexpression of p53 sequesters p300
(41)
, which may disturb the interaction of p300 with
specific transcription factors, resulting in decreased transcription of
target genes. This may be an alternative mechanism by which p53
represses transcription of hTERT. Further analyses are needed to
clarify the molecular mechanisms by which p53 represses hTERT
transcription via the proximal promoter region.
Our findings suggest a novel function of p53, although the biological significance of this function remains unclear. It is possible that p53 controls telomerase activity in normal cells and that its deregulation by p53 gene mutation, which is frequently observed in a wide variety of tumors, may contribute to increased telomerase activity in tumors. An inhibitory effect on telomerase may thus be a novel function of the antitumor activity of p53. Gene therapies targeting telomerase have been developed recently. It has been suggested that transient inhibition of telomerase activity by antisense hTR strategies leads to a rapid decrease in cell viability and tumorigenicity (42) . This effect did not require a lag period during which telomeres shorten and reach a critical length as the threshold for chromosomal instability. Telomerase may thus play roles in cell proliferation other than the maintenance of telomere length, suggesting that repression of telomerase is a promising strategy for cell growth control. These findings indicate a novel aspect of adenovirus-mediated gene transfer of p53, which effectively inhibits telomerase activity with transient but strong expression of p53.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 To whom requests for reprints should be
addressed, at Department of Obstetrics and Gynecology, School of
Medicine, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa
920, Japan. Phone: 81-0-76-265-2425; Fax: 81-0-76-234-4266; E-mail: satoruky{at}med.kanazawa-u.ac.jp 
2 The abbreviations used are: hTR, human
telomerase RNA; hTERT, human telomerase reverse transcriptase; ß-gal,
ß-galactosidase; LUC, luciferase; MOI, multiplicity of infection;
RT-PCR, reverse transcription-PCR; HPV, human papillomavirus.
Received 10/20/99; revised 1/24/00; accepted 2/ 1/00.
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