COMMUNICATION
Role for p300 in Stabilization of p53 in the Response to
DNA Damage*
Zhi-Min
Yuan,
Yinyin
Huang,
Takatoshi
Ishiko,
Shuji
Nakada,
Taiju
Utsugisawa,
Hisashi
Shioya,
Yukari
Utsugisawa,
Kazunari
Yokoyama
,
Ralph
Weichselbaum§,
Yang
Shi¶, and
Donald
Kufe
From the Dana-Farber Cancer Institute and ¶ Department of
Pathology, Harvard Medical School, Boston, Massachusetts 02115, the
Tsukuba Life Science Center, The Institute of Physical
and Chemical Research Koyadai, Tsukuba Science City 305, Japan, and the
§ Department of Radiation and Cellular Oncology, University
of Chicago, Chicago, Illinois 60637
 |
ABSTRACT |
The nuclear p300/CBP proteins function as
coactivators of gene transcription. Here, using cells deficient in p300
or CBP, we show that p300, and not CBP, is essential for ionizing
radiation-induced accumulation of the p53 tumor suppressor and thereby
p53-mediated growth arrest. The results demonstrate that deficiency of
p300 results in increased degradation of p53. Our findings suggest that
p300 contributes to the stabilization and transactivation function of
p53 in the cellular response to DNA damage.
 |
INTRODUCTION |
In the exposure of cells to ionizing radiation
(IR),1 the formation of DNA
double-strand breaks is associated with increases in p53 levels and the
transactivation function of p53 (1-3). Activation of p53 in the
response to IR induces transcription of the p21 (WAF1,
Cip-1) gene (4). Thus, the growth arrest function of p53 is
regulated at least in part by p21-mediated inhibition of cyclin-Cdk
complexes and the proliferating cell nuclear antigen (PCNA) (1). In
addition, p53-dependent induction of the bax
gene contributes to the apoptotic response to DNA damage (5). Other
genes implicated in p53-induced growth arrest and apoptosis include
GADD45 (3), mdm2 (6, 7), cyclin G (8), and
IGF-BP3 (9).
Recent work has demonstrated that the DNA-dependent protein
kinase (DNA-PK) is necessary but not sufficient for activation of p53
sequence-specific DNA binding (10). Phosphorylation of the p53
N-terminal region by DNA-PK may contribute to the transactivation function and stability of p53 (11, 12). Other studies have shown that
the ataxia telangiectasia-mutated (ATM) protein phosphorylates p53 on
serine 15 in vitro (13, 14). The findings that the p53
serine 15 site is phosphorylated in IR-treated cells (15, 16) and that
this effect is diminished in AT cells (16) have supported a role for
ATM in the regulation of p53. The p300/CBP proteins (17-20) have also
been implicated as coactivators of the p53 transactivation function
(21, 22). The N-terminal domain of p53 interacts with the C-terminal
region of p300/CBP. Acetylation of the p53 C-terminal domain by
p300/CBP stimulates the DNA binding activity of p53 (23). A dominant
negative form of p300/CBP has also been found to inhibit p53-mediated
transactivation and the G1 arrest and apoptotic responses
(24).
Cells derived from p300-deficient embryos exhibit severe defects in
proliferation (25). Consequently, in the present work, we have
established cells expressing ribozymes specific for p300 or CBP such
that the transfectants are selectively deficient in either protein. Our
results demonstrate that p300, and not CBP, is essential for IR-induced
increases in both p53 levels and the p53 transactivation function.
 |
MATERIALS AND METHODS |
Cell Culture--
MCF-7 cells were maintained in Dulbecco's
modified Eagle's medium containing 10% heat-inactivated bovine serum,
2 mM L-glutamine, 10 units/ml penicillin, and
10 µg/ml streptomycin. The active p300 (p300-R), inactive p300
(p300-RI), active CBP (CBP-R), or inactive CBP (CBP-RI) ribozymes (26)
were stably introduced into cells by LipofectAMINE (Life Technologies,
Inc.) and selection in G418. Cells were treated with ionizing radiation
at room temperature using a Gammacell 1000 (Atomic Energy of Canada)
with a 137Cs source emitting at a fixed dose rate of 0.21 Gy/min.
Immunoprecipitation and Immunoblot
Analysis--
Immunoprecipitations were performed as described (27).
Soluble proteins were incubated with anti-p300 (RW128; Upstate
Biotechnology Inc.), anti-CBP (06-294; Upstate Biotechnology Inc.) or
anti-MDM2 (Ab-1; Oncogene Science) for 1 h and precipitated with
protein A-Sepharose for an additional 1 h. The immune complexes
were washed with lysis buffer (50 mM HEPES, pH 7.5, 0.5%
Nonidet P-40, 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM sodium orthovanadate, 1 mM dithiothreitol, 1 mM NaF, 2 mM
phenylmethysulfonyl fluoride, and 10 µg/ml each of pepstatin,
leupeptin, and aprotinin). Immune complexes and lysates not subjected
to immunoprecipitation were separated by electrophoresis in
SDS-polyacrylamide gels and then transferred to nitrocellulose paper.
The filters were incubated with anti-p300, anti-CBP, anti-p53 (Ab-6;
Oncogene Science), anti-p21 (Ab-3; Oncogene Science), anti-MDM2,
anti-FLAG (M5; Eastman Kodak Co.) or anti-PCNA (SC-5b; Santa Cruz).
Proteins were detected with an ECL system (Amersham Pharmacia Biotech).
Transient Transfections--
Cells were cotransfected with: (i)
pNF-
B-Luc and pFC-MEKK (Stratagene 219077), (ii) pCRE-Luc and
pFC-PKA (Stratagene 219075), (iii) mdm2NA-Luc (28) and HA-p300, or (iv)
FLAG-p53 and HA-p300 by LipofectAMINE (Life Technologies, Inc.). Empty
vectors were used to control DNA amount. Luciferase activities were
assayed at 24 h with an enhanced luciferase assay kit (1800K;
Analytical Luminescence).
Flow Cytometry--
Cells were harvested 24 h after
IR exposure. BrdUrd was added 30 min before collection. Cells
were stained for DNA content with propidium iodide and for DNA
synthesis with a fluorescein-conjugated anti-BrdUrd antibody
(Boehringer Mannheim). Other cells were transfected with pEGFP-Ci by
LipofectAMINE. After 24 h, the cells were exposed to IR. At
24 h after IR, the cells were harvested, fixed, and the
GFP-positive cells were sorted for two-dimensional FACS analysis.
 |
RESULTS AND DISCUSSION |
Expression of the inactive p300 ribozyme (p300-RI) had no
detectable effect on p300 levels (Fig.
1A). By contrast, the active p300 ribozyme (p300-R) markedly decreased p300, and not CBP, expression (Fig. 1A). Similar results were obtained in two
independently selected cell clones (Fig. 1A). Conversely,
expression of the active CBP ribozyme (CBP-R) decreased CBP, but not
p300, levels (Fig. 1B). These findings supported specificity
of the ribozymes for selective depletion of p300 or CBP. Also, none of
the ribozymes had detectable effects on basal levels of p53 expression
(Fig. 1, A and B). The effects of deficiency in
p300 or CBP were investigated by assessing activation of the NF-
B
and CRE transcription factor pathways. NF-
B activation by MEKK was
significantly compromised in the p300-, but not in the CBP-, deficient
cells (Fig. 1C). By contrast, although stimulation of CRE
activity by protein kinase A was partially affected by deficiency in
p300, CRE activation was markedly attenuated in the CBP-deficient cells
(Fig. 1D). These findings confirm that transcriptional
coactivation functions are selectively abrogated in cells deficient in
p300 or CBP (18, 29-31).

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Fig. 1.
Association of p300 or CBP deficiency with
selective abrogation of transcriptional coactivation. A
and B, lysates from MCF-7 cells stably expressing the
inactive p300 (p300-RI), active p300 (p300-R; two
independent clones Ra and Rb), the inactive CBP (CBP-RI),
the active CBP (CBP-R; two independent clones) ribozymes
were subjected to immunoblot analysis with anti-p300, anti-CBP or
anti-p53. C and D, the indicated cell clones were
transfected in the presence of lipofectAMINE, with: 1 µg pNF- B-Luc
and 0 µg (shaded bar), 1 µg (open bar), or 3 µg (solid bar) of pFC-MEKK (Stratagene 219O77)
(C) and 1 µg of pCRE-Luc and 0 µg (shaded
bar), 1 µg (open bar), or 3 µg (solid
bar) of pFC-PKA (Stratagene 219O75) (D). Empty vector
was used to control DNA amount. Luciferase activities were assayed at
24 h. Results represent the mean ± S.D. of two experiments
each performed in triplicate.
|
|
p53 transcriptional activity was assessed with a reporter construct
containing the luciferase gene driven by a p53 enhancer from the MDM2
promoter (28). Despite similar basal levels of p53 in the cell clones,
the transactivation function of p53 was markedly decreased in the
p300-deficient cells (Fig.
2A). By contrast, there was no
apparent effect of CBP deficiency on p53 transcriptional activity (Fig.
2A). Similar results were obtained in the two independently selected p300- and CBP-deficient clones (data not shown). To confirm that the deficiency in p300 is responsible for the defect in
p53-mediated transactivation, the p300-deficient cells were
cotransfected with the luciferase reporter and a vector expressing
HA-p300. The results demonstrate that the luciferase activity is
restored in a dose-dependent manner by expression of p300
(Fig. 2B). Cotransfection of p300 with a similar reporter
driven by an MDM2 promoter with a mutated p53 binding site was
associated with little if any induction of luciferase activity (data
not shown). Whereas IR induces activation of p53, we asked whether
p300-mediated p53 transactivation is involved in the responses to IR.
The results demonstrate that exposure of p300-RI cells to IR results in
activation of p53 transcriptional activity in a
time-dependent fashion (Fig. 2C). By contrast,
IR-induced p53 transactivation was significantly attenuated in p300-R
cells. In concert with the basal transcriptional activity, deficiency in CBP did not appear to have any effect on IR-induced p53 activation. To determine whether p53 associates with the p300/CBP proteins, lysates
from wild-type MCF-7 cells were subjected to immunoprecipitation with
anti-p300 or anti-CBP. Analysis of the immunoprecipitates demonstrated
binding of p53 to p300 and not CBP (Fig. 2D).

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Fig. 2.
Deficiency of p300, but not CBP, abrogates
the p53 transactivation function. A, cells expressing
the indicated ribozymes were transfected with 1 µg of mdm2NA-Luc.
B, cells expressing p300-R were cotransfected with 1 µg of
mdm2NA-Luc and 0, 1, or 3 µg of HA-p300. Empty vector was used to
control DNA amount. Luciferase activity was assayed after 24 h.
Results represent the mean ± S.D. of two experiments each
performed in triplicate. C, cells expressing p300-RI
(solid bars), p300R (shaded bars), CBP-RI
(open bars), or CBP-R (diagonal lined bars) were
transfected with 1 µg of mdm2NA-Luc. The cells were exposed to 5-Gy
irradiation 24 h post-transfection and then harvested at the
indicated times for luciferase activity. Results represent the
mean ± S.D. of two experiments each performed in triplicate.
D, wild-type MCF-7 cells were left untreated (C)
or exposed to 5-Gy ionizing radiation (IR) and harvested
after 1 h. Lysates were subjected to immunoprecipitation with
anti-p300 or anti-CBP. The immunoprecipitates were analyzed by
immunoblotting with anti-p53 and, as controls, with anti-p300 or
anti-CBP.
|
|
To define the functional consequences of the defect in p53-mediated
transactivation in p300-deficient cells, we tested the ability of IR to
induce a G1 arrest response. Using BrdUrd labeling and
bivariate FACS analysis, we found less irradiated p300-deficient cells
arrested in G1 phase compared with similarly treated
control cells expressing the inactive ribozyme (Fig.
3A). Over 30% of the
p300-deficient cells were in S phase 24 h after receiving 5 Gy IR
compared with untreated controls. By contrast, irradiated CBP-deficient
cells were less affected, with the S phase population being
approximately 10% of untreated samples (Fig. 3, A and
B). Similar results were obtained with the independently
isolated p300- and CBP-deficient clones (data not shown). To confirm
that p300 deficiency is responsible for the defective G1
arrest response, the p300-deficient cells were transfected with the
empty vector or HA-p300. The results demonstrate that the response to
irradiation was restored by expression of p300 (Fig. 3C).
These findings indicate that p300, and not CBP, is necessary for the
G1 arrest response to IR.

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Fig. 3.
p300, and not CBP, is necessary for the
p53-mediated G1 arrest response to IR. A,
representative two-dimensional FACS analysis of cells expressing the
indicated ribozymes 24 h after exposure to 0- or 5-Gy IR.
B, percentage of S phase cells after IR relative to
unirradiated cells. Results represent the mean ± S.D. from two
experiments each performed in triplicate. C, cells
expressing the p300-RI or p300-R ribozymes were transfected with 0.5 µg of pEGFP-Ci (lanes 1 and 2), and cells
expressing p300-R were cotransfected with 3 µg of empty vector and
0.5 µg of pEGFP-Ci (lane 3) or HA-p300 and 0.5 µg of
pEGFP-Ci (lane 4). After 24 h, the cells were exposed
to 0- or 5-Gy irradiation. After an additional 24 h, the cells
were harvested, fixed, and the GFP-positive cells were sorted for
two-dimensional FACS analysis. Results represent the percentage of S
phase cells (mean ± S.D. of two experiments performed in
triplicate) after IR relative to unirradiated cells.
|
|
Whereas IR-induced G1 growth arrest is impaired in
p300-deficient cells, we asked whether this defect is due to a decrease in the transactivation function of p53. The results demonstrate that
both the accumulation of p53 and the induction of p21 and MDM2 in
response to IR are attenuated in the p300-deficient cells, but not in
the CBP-deficient or control cells (Fig.
4A). To confirm that the
deficiency in p300 is responsible for the impaired p53 response to IR,
we transfected the p300-deficient cells with HA-p300. Transfection of
HA-p300, but not the empty vector, restored IR-induced accumulation of
p53 and the transactivation of p21 and MDM2 (Fig. 4B). These
findings suggest that the attenuated accumulation of p53 and the
impaired induction of p21 in p300-deficient cells are responsible for
the defect in IR-induced G1 arrest. Because DNA
damage-induced accumulation of p53 is regulated by a post-translational mechanism (1), the attenuated induction of p53 in irradiated p300-deficient cells prompted studies on p53 stability. FLAG-tagged p53
was cotransfected with a control vector or HA-p300 into p300-deficient cells. Stability of the FLAG-tagged p53 was assessed after the addition
of cycloheximide. Comparison of the declines in p53 levels under the
different experimental conditions demonstrates that p300 stabilizes the
p53 protein (Fig. 4C). MDM2 binds to p53 in the
transactivation domain and promotes p53 degradation (32-34). To
determine whether p300 affects the formation of p53-MDM2 complexes, anti-MDM2 immunoprecipitates were subjected to immunoblotting with
anti-p53. The results demonstrate that the association between p53 and
MDM2 is similar before and after irradiation in the p300-RI and p300-R
cells (Fig. 4D). These findings suggest that p300 stabilizes p53 by a mechanism that is not involved in disassociation of the p53-MDM2 complex.

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Fig. 4.
p300 regulates accumulation of p53.
A, cells expressing the indicated ribozymes were left
untreated (C) or were exposed to 5-Gy ionizing radiation
(IR). Lysates from cells harvested 3 h afer IR were
subjected to immunoblot analysis with anti-p53, anti-p21, or anti-MDM2.
B, p300-deficient cells were transfected with 3 µg of
control vector or HA-p300. After 24 h, the cells were treated and
analyzed as described in A. C, p300-deficient
cells were cotransfected with 3 µg of control vector and 1 µg of
FLAG-p53 or with 3 µg of HA-p300 and 0.5 µg of FLAG-p53 to achieve
comparable FLAG-p53 expression levels. After 24 h, the cells were
treated with 10 µg/ml cycloheximide and then harvested at the
indicated times. Lysates were subjected to immunoblot analysis with
anti-FLAG or anti-PCNA. D, cells expressing the p300-RI or
p300-R ribozymes were left untreated (C) or exposed to 5-Gy
ionizing radiation (IR) and harvested 1 h later.
Lysates were subjected to immunoprecipitation with a limiting amount of
anti-MDM2. The immunoprecipitates were analyzed by immunoblotting with
anti-p53 and anti-MDM2.
|
|
Our results obtained with cells deficient in p300 or CBP indicate that
p53-dependent transactivation is mediated by a
p300-dependent, CBP-independent mechanism. Whereas our
findings in CBP-deficient cells suggest that CBP is not involved in
induction of MDM2 expression, other studies have shown that transient
overexpression of CBP potentiates activation of the mdm2
gene by p53 (21). Indeed, we also found that transient overexpression
of CBP in the p300-deficient cells restores in part the transcriptional
coactivation of p53 (data not shown). These findings suggest that
results obtained in transient overexpression or gain of function
studies may confound interpretation of events observed in cells with
loss or deficiency of function. In this context, p300-, but not CBP-,
deficient cells exhibit defects in induction of p21 and MDM2 in the
response to DNA damage. These results are in concert with the
observation that p300, and not CBP, associates with p53 in cells. We
show that p300, and not CBP, is required for the IR-induced
accumulation of p53. The results indicate that p300 functions in the
stabilization of p53. Thus, our findings collectively support a model
in which p300 stabilizes p53 and contributes to the p53 transactivation function in the growth arrest response to DNA damage.
 |
ACKNOWLEDGEMENTS |
We thank Dr. David Livingston (Dana-Farber
Cancer Institute) for the p300 expression construct and Dr. Zhi-Xiong
Xiao (Boston University) for the MDM2 expression construct.
 |
FOOTNOTES |
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
The abbreviations used are:
IR, ionizing
radiation; PCNA, proliferating cell nuclear antigen; PK, protein
kinase; ATM, ataxia telangiectasia-mutated; Gy, gray; BrdUrd, bromodeoxyuridine; GFP, green fluorescence protein; FACS, fluorescence-activated cell sorting.
 |
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