Previous Article | Next Article 
J Virol, April 1998, p. 3221-3226, Vol. 72, No. 4
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Evidence of a Role for Phosphatidylinositol 3-Kinase Activation
in the Blocking of Apoptosis by Polyomavirus Middle T Antigen
Jean
Dahl,1
Annmarie
Jurczak,1
Linda A.
Cheng,1
David C.
Baker,2 and
Thomas L.
Benjamin1,*
Department of Pathology, Harvard Medical
School, Boston, Massachusetts 02115,1 and
Department of Chemistry, The University of Tennessee,
Knoxville, Tennessee 379962
Received 29 August 1997/Accepted 12 December 1997
 |
ABSTRACT |
A polyomavirus mutant (315YF) blocked in binding
phosphatidylinositol 3-kinase (PI 3-kinase) has previously been shown
to be partially deficient in transformation and to induce fewer tumors and with a significant delay compared to wild-type virus. The role of
polyomavirus middle T antigen-activated PI 3-kinase in apoptosis was
investigated as a possible cause of this behavior. When grown in medium
containing 1D-3-deoxy-3-fluoro-myo-inositol to
block formation of 3'-phosphorylated phosphatidylinositols, F111 rat
fibroblasts transformed by wild-type polyomavirus (PyF), but not normal
F111 cells, showed a marked loss of viability with evidence of
apoptosis. Similarly, treatment with wortmannin, an inhibitor of PI
3-kinase, stimulated apoptosis in PyF cells but not in normal cells.
Activation of Akt, a serine/threonine kinase whose activity has been
correlated with regulation of apoptosis, was roughly twofold higher in
F111 cells transformed by either wild-type virus or mutant 250YS
blocked in binding Shc compared to cells transformed by mutant 315YF.
In the same cells, levels of apoptosis were inversely correlated with
Akt activity. Apoptosis induced by serum withdrawal in Rat-1 cells
expressing a temperature-sensitive p53 was shown to be at least
partially p53 independent. Expression of either wild-type or 250YS
middle T antigen inhibited apoptosis in serum-starved Rat-1 cells at
both permissive and restrictive temperatures for p53. Mutant 315YF
middle T antigen was partially defective for inhibition of apoptosis in
these cells. The results indicate that unlike other DNA tumor viruses
which block apoptosis by inactivation of p53, polyomavirus achieves
protection from apoptotic death through a middle T antigen-PI
3-kinase-Akt pathway that is at least partially p53 independent.
| |
INTRODUCTION |
Programmed cell death occurs during
normal development and under certain pathological conditions. In
mammalian cells, apoptosis can be induced by a variety of stimuli,
including DNA damage (45), virus infection (54,
57), oncogene activation (25), and serum withdrawal
(34, 37). Apoptosis can also be blocked by a number of
factors, including adenovirus E1B 55- or 19-kDa proteins (9,
16), baculovirus p35 and iap genes (10),
Bcl-2 (36, 61), and survival factors (12, 21).
DNA tumor viruses have evolved mechanisms that both trigger and inhibit
apoptosis. These frequently involve binding and inactivation of tumor
suppressor proteins. E7 in some papillomaviruses (22), E1A
in adenovirus (31, 43, 64), and large T antigen in simian
virus 40 (SV40) (17) bind Rb and/or p300 and lead to
upregulation of p53, which is thought to trigger apoptosis in
virus-infected cells. The same viruses also inhibit apoptosis by
inactivating p53 by various mechanisms (44, 63, 67). In
contrast, the mechanism by which polyomavirus interacts with apoptotic
pathways in the cell is not known; no direct interaction with p53 by
any of the proteins encoded by this virus has been demonstrated
(19, 62).
The principal oncoprotein of polyomavirus is the middle T antigen.
Neoplastic transformation by polyomavirus middle T antigen has as a
central feature its association with and activation of members of the
Src family of tyrosine kinases p60c-src
(13) and p62c-yes (42).
The major known consequence of these interactions is phosphorylation of
middle T antigen on specific tyrosine residues creating binding sites
for other signaling proteins. Phosphorylation at tyrosines 250, 315, and 322 promotes binding to Shc (18), the p85 regulatory
subunit of phosphatidylinositol 3-kinase (PI 3-kinase) (59),
and phospholipase C
-1 (58), respectively. Recognition of
multiple signaling pathways emanating from middle T antigen has led to
a keen interest in identifying their downstream biochemical effects,
which collectively lead to the emergence of neoplastic transformation
and presumably underlie the dramatic ability of the virus to induce
many kinds of tumors in the mouse.
Previous work has shown that the binding of PI 3-kinase to middle T
antigen is essential for full transformation of rat fibroblasts in
culture (8) and for rapid development of a broad spectrum of
tumors in mice (30), for translocation of the GLUT1
transporter (68), and activation of p70 S6 kinase
(14). While the mutant 315YF (blocked in PI 3-kinase
activation) was able to induce some tumors, it did so at reduced
frequencies and with an average latency three times longer than that of
either the wild-type virus or a mutant, 250YS, blocked in binding Shc
(4, 30). Recent studies have indicated a role of PI 3-kinase
in blocking apoptosis in nonviral systems. Growth factor receptors
acting through protein tyrosine kinases may prevent apoptosis by
activating PI 3-kinase in PC12 cells, T lymphocytes, hematopoietic
progenitors, and rat fibroblasts (7, 48, 56, 65, 66). The
failure of mutant 315YF to induce full transformation of cells in
culture and to induce the rapid development of tumors in mice could
therefore be related, at least in part, to a failure to block
apoptosis. In this study, we focus on the question of whether middle T
antigen-PI 3-kinase interaction is involved in blocking apoptosis in
cells transformed by polyomavirus.
| |
MATERIALS AND METHODS |
Cells.
Rat F111 cells, as well as PyF, PyF-315YF, and
PyF-250YS cell lines derived from F111 cells, were described previously
(14). Cells were routinely cultured in Dulbecco's modified
Eagle medium (DMEM) containing 10% calf serum, 0.375% sodium
bicarbonate, 100 U of penicillin, and 100 µg of streptomycin per ml
in a 5% CO2 atmosphere at 37°C. Rat-1 clones stably
expressing vector alone (Neo), wild-type, 315YF, and 250YS middle T
antigens were prepared by electroporation of Rat-1 cells with defective
murine retroviral vectors containing the cloned middle T antigen genes
(15, 68). Stably transfected cells were selected with
Geneticin (G418) at 400 µg/ml, and clones were isolated by limiting
dilution. To establish cell lines expressing temperature-sensitive p53
(p53val135), pBabepuro was cotransfected with a 10-fold excess of
pLTRcGp53val135 (47) by electroporation into Rat-1 clones
stably expressing vector alone (Neo), wild-type, 315YF, and 250YS
middle T antigens. Cells were selected with 2 µg of puromycin per ml
and cloned by limiting dilution. Cell lines expressing similar levels
of middle T antigen or p53val135 were maintained in DMEM supplemented
with 10% calf serum, sodium bicarbonate, penicillin-streptomycin, 100 µg of G418 per ml, and 0.5 to 1 µg of puromycin per ml.
Cell growth assays.
Cells plated at a density of 4 × 103 cells per well in 96-well plates were grown for 4 days
in myo-inositol-free DMEM (GIBCO) supplemented with 10%
calf serum, 5 µM myo-inositol, and increasing levels of
1D-3-deoxy-3-fluoro-myo-inositol
(38). Viable cells were assayed with the MTT
(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay
(49).
[3H]1D-3-deoxy-3-fluoro-myo-inositol
was obtained from Moravek Biochemicals, Inc.
Ca2+ uptake assays.
To measure Ca2+
uptake, cells grown in myo-inositol-free DMEM supplemented
with 10% dialyzed calf serum, 5 µM myo-inositol and 2 mM
analog for 72 h were changed to 20 mM HEPES (pH 7.4), 150 mM NaCl,
5 mM KCl, 1 mM MgCl2, 50 µM
K2HPO4, and 0.1% glucose (buffer A) containing
0.1 mM CaCl2. The reaction was started by adding 2 µCi of
45Ca2+ (NEN) per ml and 100 µM
lysophosphatidic acid. After 1 min, the cells were washed five times
with buffer A containing 10 mM CaCl2 and solubilized in 1%
sodium dodecyl sulfate for scintillation counting and protein
determination (bicinchoninic acid assay; Pierce).
Apoptosis assays.
To measure the effect of the
myo-inositol analog on apoptosis, F111 and PyF cells were
plated on coverslips at a density of 5 × 104 cells
per well in 9.6-cm2 wells. After 2 days, the medium was
changed to myo-inositol-free DMEM supplemented with 10%
dialyzed calf serum, 5 µM myo-inositol, and 2 mM analog,
and cells were then grown for 2 days. To measure the effect of serum
starvation on apoptosis, 1 × 105 to 4 × 105 cells were plated on coverslips in 8-cm2
plates and grown to 60 to 80% confluence. Cells were washed twice with
serum-free medium and incubated at the appropriate temperature. Rat-1
clones expressing p53val135 were cultured at 38.5°C before temperature shift. 4',6-Diamidino-2-phenylindole (DAPI) staining and
the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end
labeling (TUNEL) assay (Oncor) with attached cells were used to detect
apoptotic cells.
Kinase assays.
PI 3-kinase activity in immune complexes
prepared with anti-T serum was assayed as described previously
(14). Akt kinase was assayed as described previously
(20) with histone H2B as the substrate. Cell lysates used
for Akt kinase assays were prepared with 20 mM Tris (pH 7.4), 140 mM
NaCl, 1% Nonidet P-40, 10 mM NaF, 1 mM Na3VO4,
1 mM EDTA, 1 mM phenylmethylsulfonyl fluoride, 25 µg of leupeptin per
ml, and 10 µg of aprotinin per ml. Polyclonal antibody 31 to Akt (M. Birnbaum, HHMI, University of Pennsylvania School of Medicine) was used
to prepare Akt immune complexes. Akt kinase activity was quantitated
with a Molecular Imager (Bio-Rad).
| |
RESULTS |
1D-3-Deoxy-3-fluoro-myo-inositol inhibits
net growth and stimulates apoptotic death in polyomavirus transformed
but not in nontransformed F111 rat fibroblasts.
Analogs of
myo-inositol with substitution at the D-3
position are potential antagonists for cells exhibiting a
constitutively activated PI 3-kinase and are known to inhibit growth of
v-sis-transformed NIH 3T3 cells (52). Several
studies have shown that
1D-3-deoxy-3-fluoro-myo-inositol acts as a
substrate for mammalian phosphatidylinositol synthase and is
incorporated into phosphatidylinositols (38, 51, 52). Signaling via phosphatidylinositol 4,5-bisphosphate and phospholipase C
appears to be unaffected by the analog, as indicated by the response of
intracellular calcium levels to growth factors (52).
To determine the effect of
1D-3-deoxy-3-fluoro-myo-inositol on the growth
of nonvirus-transformed (F111) and polyomavirus-transformed F111
fibroblasts (PyF) (14, 26), cells were grown with increasing levels of 1D-3-deoxy-3-fluoro-myo-inositol
(38). The data in Fig. 1 show
that PyF cells exhibited marked growth inhibition compared to F111
cells when grown in the presence of
1D-3-deoxy-3-fluoro-myo-inositol (up to 4 mM).
Differences in viability were not due to differences in uptake, since
studies showed that the analog was incorporated into phospholipid
equally well by both cell types (data not shown).
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FIG. 1.
Growth of cells in the presence of
1D-3-deoxy-3-fluoro-myo-inositol. Normal F111
( ) and polyomavirus-transformed PyF ( ) cells were plated at
subconfluency in myo-inositol-free DMEM containing 10%
dialyzed calf serum, 5 µM myo-inositol, and
1D-3-deoxy-3-fluoro-myo-inositol at the
concentrations shown and grown for 4 days. Growth was measured by the
MTT viability assay as described in Methods and Materials and plotted
as a percentage of that of the control without
1D-3-deoxy-3-fluoro-myo-inositol.
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|
The effect of the analog on phospholipase C-dependent pathways was
studied by measuring Ca
2+ uptake induced by
lysophosphatidic acid (
40) and was found
to be similar in
cells grown in the absence or presence of
1
D-3-deoxy-3-fluoro-
myo-inositol
(Fig.
2). Taken together, the data show that
while normal and
transformed cells take up the 3-deoxy-3-fluoro analog
of
myo-inositol
equally, the growth inhibitory effect was
more evident in transformed
cells. The effect of the inositol analog on
cell viability was
apparently unrelated to signal transduction via
phospholipase
C. Previous work has shown that an increased level of
inositol
triphosphate in cells expressing wild-type middle T antigen is
dependent on p60
c-arc but independent of PI
3-kinase activation (
33).
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FIG. 2.
Effect of
1D-3-deoxy-3-fluoro-myo-inositol on
45Ca2+ uptake induced by lysophosphatidic acid
in F111 and PyF cells. Cells were grown on medium containing 5 µM
myo-inositol with or without 2 mM
1D-3-deoxy-3-fluoro-myo-inositol for 3 days.
45Ca2+ uptake was measured in the absence (open
bars) or presence (hatched bars) of 100 µM lysophosphatidic acid.
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|
To determine whether the
myo-inositol analog induced
apoptosis preferentially in PyF cells, F111 and PyF cells were
subjected
to DAPI staining and the TUNEL assay after growing on 2 mM
analog
(Fig.
3A). In the presence of
1
D-3-deoxy-3-fluoro-
myo-inositol,
the percentage
of apoptosis of PyF cells rose nearly threefold
over the level seen in
the absence of analog, whereas that of
F111 cells remained unchanged
(Fig.
3B). These results show that
blocking the PI 3-kinase pathway in
cells transformed by wild-type
polyomavirus drives cells toward
apoptosis.
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FIG. 3.
Effect of 3-deoxy-3-fluoro-myo-inositol on
apoptosis. (A) DAPI and TUNEL staining of PyF cells showing DNA
condensation and fragmentation. (B) Percentage of apoptotic cells in
cultures grown for 2 days on medium containing 5 µM
myo-inositol (open bars) or 5 µM myo-inositol
and 2 mM 1D-3-deoxy-3-fluoro-myo-inositol
(hatched bars) and quantitated by counting >1,000 cells in duplicate
experiments.
|
|
Wortmannin stimulates apoptosis in polyomavirus-transformed but not
nontransformed F111 cells.
Further evidence that PI 3-kinase helps
to prevent apoptosis in polyomavirus-transformed cells was sought by
using wortmannin, a potent inhibitor of PI 3-kinase both in vivo and in
vitro (53, 60). F111 and PyF cells growing in 10% calf
serum were treated with increasing concentrations of wortmannin for
2 h before fixation. TUNEL-positive PyF cells were observed with
>10 nM wortmannin, whereas F111 cells failed to undergo apoptosis
after treatment with wortmannin at concentrations up to 1,000 nM (Fig.
4A). Wortmannin was shown to inhibit in
vitro PI 3-kinase of PyF cells with a similar sensitivity (Fig. 4B).
The results support the involvement of PI 3-kinase in preventing
apoptosis in cells transformed by polyomavirus but not in
nonvirus-transformed F111 cells.
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FIG. 4.
Effect of wortmannin on apoptosis of F111 () and PyF
() cells (A) and in vitro PI 3-kinase activity in anti-T-antigen
immunoprecipitates of PyF () cell extracts (B). Cells growing on
DMEM containing 10% calf serum were treated with wortmannin for 2 h before fixation for DAPI and the TUNEL assay. The percentage of
apoptotic cells was quantitated by counting >1,000 cells in duplicate
experiments.
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Activation of Akt requires binding of PI 3-kinase to middle T
antigen in F111 cells transformed by polyomavirus.
Phosphatidylinositol 3,4-bisphosphate, a product of PI 3-kinase,
directly regulates Akt (27), the serine/threonine kinase also designated PKB or Rac (2, 11, 39). Akt has been
implicated in inhibition of apoptosis by serum and certain growth
factors (5, 20, 41). Receptors blocked in PI 3-kinase
binding fail to activate Akt (28), and dominant negative Akt
expression induces apoptosis (20). To determine whether
transformation by polyomavirus leads to activation of Akt, in vitro
kinase assays of Akt immunoprecipitates were performed with extracts
from serum-starved cells. Akt activity, shown in Fig.
5, was roughly twofold higher in cells
transformed by wild-type and 250YS polyomavirus than in parental F111
cells or cells transformed by mutant 315YF. The level of constitutive activation in PyF approached maximal levels achieved by adding back
15% serum. The levels of phosphatidylinositol 3,4-bisphosphate are
known to be elevated in 250YS and wild-type middle T antigen-expressing F111 cells compared to 315YF middle T antigen-expressing cells (14). When F111 cells expressing wild-type or mutant middle T antigens were serum starved and examined for apoptosis, cells expressing 315YF showed a twofold elevation in the percentage of
apoptotic cells over the percentage seen in either wild-type or 250YS
middle T antigen-expressing cells. These data suggest that activation
of Akt depends on binding of PI 3-kinase to middle T antigen and
correlates with inhibition of apoptosis.
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FIG. 5.
In vitro activation of Akt by polyomavirus middle T
antigen. Akt was immunoprecipitated from lysates prepared from cells
that had been starved for serum for 24 h. F111, normal rat
fibroblasts; PyF, F111 cells transformed by wild-type virus; PyF-315YF,
F111 cells transformed by 315YF virus; PyF-250YS, F111 cells
transformed by 250YS virus. Data are averaged from two to seven
experiments. Error bars show standard deviations.
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|
Wild-type middle T antigen blocks apoptosis induced by serum
withdrawal in Rat-1 cells by a p53-independent process.
Rat-1
cells are dependent upon serum for survival and undergo apoptosis when
treated with wortmannin (65). To extend the finding of a
role for PI 3-kinase in the prevention of apoptosis by middle T
antigen, Rat-1 cells were transformed with retroviral vectors encoding
wild-type or mutant middle T antigens and selected with G418. In an
attempt to determine if the apoptotic response of these cells is p53
dependent, clones stably expressing the middle T antigens were also
transfected with a temperature-sensitive p53 gene, p53val135
(47), and selected for puromycin resistance. p53val135
behaves like a dominant inhibitory mutant at the restrictive temperature (38.5°C) and exhibits wild-type function at 32°C. At
38.5°C, p53val135 cooperates with E1A or ras to transform
primary cells which also express wild-type endogenous p53 (16, 35, 47). p53val135 is impaired in transcription activation
(23), repression (1), and nuclear translocation
(6, 32, 46) at the nonpermissive temperature.
To determine the effect of p53 on apoptosis, all clones were grown with
10% calf serum at 38.5°C and either fixed for apoptosis
assays at
0 h or grown for 2 days more either at 38.5°C in serum-free
medium or at 32°C in medium with or without calf serum and then
fixed
(Fig.
6). On shifting to 32°C in the
presence of serum,
there was only a slight increase in the percentage
of apoptotic
cells in all clones. However, when normal cells or cells
expressing
315YF mutant middle T antigen were shifted down and the
serum
was removed, there was roughly a 10-fold increase in the percent
of apoptotic cells after 2 days. Cells expressing either wild-type
middle T antigen or mutant 250YS middle T antigen showed a roughly
threefold increase in apoptotic cells under the same conditions,
indicating an effect of middle T antigen-activated PI 3-kinase
in
partially blocking the apoptotic response brought on by serum
withdrawal. Protection against apoptotic death upon serum withdrawal
by
wild-type and 250YS middle T antigens was not significantly
temperature
sensitive in any of the clones. The protection afforded
by middle T
antigen-PI 3-kinase interaction thus appeared to be
p53 independent,
at least to a large extent.
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FIG. 6.
Serum starvation-induced apoptosis in Rat-1 clones
expressing p53val135 along with the neomycin resistance vector alone
(Neo [control]) or T antigens (wild type [WT], 315YF, or 250YS).
Four plates of each cell type were grown in DMEM containing 10% calf
serum at 38.5°C to 70% confluence. Two plates remained in 10%
serum, and two plates were changed to serum-free medium. Cells in 10%
serum were either fixed at 0 h (solid bars) or shifted to 32°C
(vertically striped bars) and fixed at 48 h. Cells in 0% serum
either remained at 38.5°C (hatched bars) or were shifted to 32°C
(open bars), and then both were fixed at 48 h. Data are averaged
from four to seven separate experiments. Error bars show the standard
errors of the means.
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| |
DISCUSSION |
Apoptosis in F111 rat fibroblasts transformed by polyomavirus is
shown to be enhanced when PI 3-kinase activity is inhibited by either
growth of cells on
1D-3-deoxy-3-fluoro-myo-inositol or treatment
with wortmannin, indicating involvement of PI 3-kinase in blocking
apoptosis. In contrast, normal F111 cells are much less dependent on PI
3-kinase for survival, as indicated by their resistance to death
induced by the myo-inositol analog and by wortmannin.
Transformation of F111 by polyomavirus mutant 315YF blocked in
activation of PI 3-kinase significantly enhances the susceptibility of
these cells to apoptosis induced by serum withdrawal compared to that
in cells transformed by the wild-type or 250YS polyomavirus that
encodes middle T antigens that activate PI 3-kinase. Cells transformed
by mutant 315YF also have a lower constitutive activity of Akt, a
serine/threonine kinase regulated by phosphatidylinositol 3,4-bisphosphate (27) and known to be associated with
regulation of apoptosis (20, 41). This suggests that signal
transduction via middle T antigen through PI 3-kinase and Akt is
important for survival and protection from apoptosis.
In contrast to F111 rat fibroblasts, nontransformed Rat-1 fibroblasts
show a marked serum dependence for survival and are susceptible to
wortmannin-induced apoptosis (65). Apoptosis induced by
serum withdrawal in Rat-1 cells expressing p53val135 appears to be
principally p53 independent, since the level of apoptosis at 32°C is
not significantly higher than that at 38.5°C. In Rat-1 cells
expressing wild-type or 250YS middle T antigen, there is significant
protection against apoptosis upon serum withdrawal and the degree of
protection is largely temperature independent. Rat-1 cells expressing
315YF mutant middle T antigen show less protection against apoptotic
death, indicating a role of PI 3-kinase in blocking apoptosis under
these conditions. While Rat-1 cells stably transfected with
pLTRcGp53val135 possibly retain a low level of functional p53 at the
nonpermissive temperature, which might arise either from unquenched
endogenous wild-type p53 or p53val135 that retains partial wild-type
activity, the absolute amount of functional p53 should be markedly
lower at 38.5°C than at 32°C. Consistent with our findings, p53
independence of apoptosis induced by serum withdrawal has also been
observed in other cell types (3, 24, 37, 55).
The ability of a virus to delay host cell death is thought to be
essential for virus growth (54). Whether polyomavirus can block apoptosis has been unclear. Other DNA tumor viruses, such as
adenovirus and SV40, inhibit programmed cell death by inactivation of
p53. Since polyomavirus has no known direct interaction with p53
(19), a separate antiapoptotic mechanism is indicated. The results presented here indicate that in polyomavirus-infected cells,
middle T antigen, acting through PI 3-kinase and Akt, blocks apoptosis.
Interestingly, viruses that handle p53 directly by inactivation or
degradation (i.e., adenovirus, SV40, and papillomavirus) lack direct
mechanisms for activating PI 3-kinase. Recent evidence suggests that PI
3-kinase and Akt block apoptosis by inhibiting the Ced3/ICE-like
activity (41), and Ced3/ICE-like proteases are thought to
lie on apoptotic pathways downstream of both p53 (43) and
the FAS pathway (50).
Mutant 315YF polyomavirus, whose middle T antigen fails to bind PI
3-kinase, is associated with delayed appearance of tumors in neonatally
infected mice (8, 14, 29). In contrast, the 250YS mutant,
whose middle T antigen binds PI 3-kinase but fails to bind Shc, induces
tumors broadly and with little or no delay compared to wild-type virus
(4). The delay in tumor induction by the mutant 315YF may be
due to failure to protect against apoptosis in the lytic phase of viral
growth or in tumor development.
| |
ACKNOWLEDGMENTS |
We thank Geoffrey Cooper for providing Rat-1 cells, Phil
Hinds for providing the temperature-sensitive p53 expression
plasmid pLTRcGp53val135, and Morris Birnbaum for providing
anti-Akt.
This work was supported by grants from the National Cancer Institute to
T.L.B. (R35-CA44343) and D.C.B. (R01-CA45795).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Pathology, Harvard Medical School, 200 Longwood Ave., D2-230, Boston, MA 02115. Phone: (617) 432-1960. Fax: (617) 277-5291. E-mail: tbenjamin{at}warren.med.harvard.edu.
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J Virol, April 1998, p. 3221-3226, Vol. 72, No. 4
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
