COMMUNICATION
p53 Inhibits Hypoxia-inducible Factor-stimulated
Transcription*
Mikhail V.
Blagosklonny
§,
Won G.
An¶
,
Larisa
Y.
Romanova**,
Jane
Trepel¶,
Tito
Fojo
, and
Len
Neckers¶
From the Departments of
Experimental Therapeutics and
¶ Cell and Cancer Biology, Medicine Branch and ** Laboratory of
Genetics, NCI, National Institutes of Health,
Bethesda, Maryland 20892
 |
ABSTRACT |
p53 is required for hypoxia-induced apoptosis
in vivo, although the mechanism by which this occurs is not
known. Conversely, induction of the hypoxia-inducible factor-1 (HIF-1)
transactivator stimulates transcription of a number of genes crucial to
survival of the hypoxic state. Here we demonstrate that p53 represses
HIF-1-stimulated transcription. Although higher levels of p53 are
required to inhibit HIF than are necessary to transcriptionally
activate p53 target genes, these levels of p53 are similar to those
that stimulate cleavage of poly(ADP-ribose) polymerase, an early event
in apoptosis. Transfection of full-length p300 stimulates both
p53-dependent and HIF-dependent transcription
but does not relieve p53-mediated inhibition of HIF. In contrast, a
p300 fragment, which binds to p53 but not to HIF-1, prevents
p53-dependent repression of HIF activity. Transcriptionally
inactive p53, mutated in its DNA binding domain, retains the ability to
block HIF transactivating activity, whereas a transcriptionally
inactive double point mutant defective for p300 binding does not
inhibit HIF. Finally, depletion of doxorubicin-induced endogenous p53
by E6 protein attenuates doxorubicin-stimulated inhibition of HIF,
suggesting that a p53 level sufficient for HIF inhibition can be
achieved in vivo. These data support a model in which
stoichiometric binding of p53 to a HIF/p300 transcriptional complex
mediates inhibition of HIF activity.
 |
INTRODUCTION |
The p53 tumor suppressor protein mediates both growth arrest and
apoptosis. Whereas p53-dependent growth arrest requires
transcriptional activation of p21WAF1/CIP1
(1-3), substantial data have accumulated that transactivating capability is not necessary for p53 to stimulate apoptosis (4-6).
Hypoxia is perhaps the most physiologic inducer of p53 (7), and
hypoxia-mediated apoptosis of tumors in vivo requires p53 (8). Indeed, p53 is the most frequently inactivated gene in solid
tumors, and in animal tumor models, hypoxia selects against wild type
p53 (8). However, the mechanism by which p53 mediates apoptosis in
hypoxic tumor cells is not known. Hypoxic conditions in
vitro as well as in vivo result in induction of
hypoxia-inducible factor-1
(HIF-1
),1 the limiting,
hypoxia-inducible subunit of the HIF-1 transactivator (9). HIF-1, in
turn, stimulates transcription of a number of genes important for tumor
survival under hypoxic conditions in vivo, including
vascular endothelial growth factor (VEGF), erythropoietin (Epo), and
several glycolytic enzymes (10). Tumors in which hypoxia cannot induce
HIF-1 transcriptional activity remain small and fail to metastasize
(11).
We have recently shown that hypoxic induction of p53 requires
concomitant induction of HIF-1
, and that HIF-1
binds to and stabilizes p53 (12). We found previously that HIF-1
had no direct
effect on p53 transcriptional activity. We now report that association
of HIF-1
and p53 results in inhibition of HIF-stimulated transcription. This requires a higher p53 level than is necessary for
transcriptional activation of several endogenous p53-responsive promoters but correlates well with the level of p53 necessary to cause
apoptosis.
 |
MATERIALS AND METHODS |
Cell Lines--
SKBr3 and MCF7 are human breast cancer cell
lines obtained from American Type Culture Collection (Rockville, MD),
and PC3M is a highly metastatic variant of the prostate cancer cell
line, PC3. SKBr3 contains one mutated, transcriptionally inactive p53 allele, MCF7 contains transcriptionally active wild type p53 (wtp53), and PC3M cells are p53-null.
Reagents and Plasmids--
Ad-LacZ, a
-galactosidase-expressing, replication-deficient adenovirus, and
Ad-p53, a wtp53-expressing, replication-deficient adenovirus, were
obtained from B. Vogelstein (Johns Hopkins Oncology Center). Viral
titer was determined as described previously (13). Multiplicity of
infection (MOI) is defined as the ratio of total number of viruses used
in a particular infection per number of cancer cells to be infected
(i.e. number of viruses per cell).
Plasmids WWP-Luc, a p21 promoter-luciferase construct, PG13-Luc,
containing a generic p53 response element, pCMV
.wtp53, and the p53
mutant p53-273H were obtained from B. Vogelstein. Bax-Luc, a Bax
promoter-luciferase construct and the p53 double point mutant p53(22/23) were obtained from K. Vousden (ABL Basic Research Program, NCI-FCRDC). The pCMV
.HA-HIF-1
expression plasmid was obtained from D. Livingston (Dana Farber Cancer Institute). An HIF-responsive, VEGF promoter-derived luciferase construct containing four amplified HIF-1 binding sites (VEGF-Luc), inserted into a pGL2-promoter vector
was obtained from A. J. Giaccia (Stanford University) and described previously (14). An HIF-responsive, erythropoietin promoter-derived luciferase construct (Epo-Luc) and its HIF-insensitive mutant variant (mEpo-Luc), inserted into a pGL3-Promoter vector were
obtained from F. Bunn and E. Huang (Harvard Medical School). The
control luciferase plasmid, pGL2-control, driven by SV40 promoter and
enhancer sequences, was purchased from Promega Corp. (Madison, WI). The
full-length p300 expression plasmid, pCMV
.p300, and the p53-binding
p300 fragment, pCMV
.p300(1514-1922), were obtained from K. Kelly
(NCI). pCMV.
-galactosidase was purchased from
CLONTECH (Palo Alto, CA). pCMV.neo16E6 was obtained
from K. Vousden.
Transient Transfection Assay--
8 × 105 or
4 × 106 cells were plated in T25 flasks or 6-well
plates (Costar, Acton, MA), respectively. The next day, cells were transfected with plasmids in the presence of LipofectAMINE (Life Technologies, Inc.). After 6-12 h of incubation with the plasmid-lipid suspension, the medium was changed, and cells were grown for an additional 24 h, unless otherwise indicated. The cells were
lysed and analyzed for luciferase activity as described
previously (12).
Western Blot Analysis--
Proteins were resolved with 8%
SDS-polyacrylamide gel electrophoresis for detection of p53, Mdm-2, and
poly(ADP-ribose) polymerase (PARP) as described previously (15).
DNA Synthesis--
DNA synthesis was monitored by
[3H]thymidine incorporation (13).
 |
RESULTS AND DISCUSSION |
Wild Type p53 Abrogates HIF-1
Activity--
We initially
investigated the effects of wtp53 on HIF-1-responsive transcription in
SKBr3 and PC3M cell lines. Transient expression of HIF-1 dramatically
induced transcription of two HIF-dependent reporter
constructs, Epo-Luc (containing an HIF-responsive element from the
erythropoietin gene) and VEGF-Luc (containing HIF-responsive elements
from the VEGF gene) in both cell lines, whereas co-transfection of
wtp53 abrogated this induction (Fig. 1,
A, B, and D). Dose-response analysis
showed near-maximal inhibition of HIF-1-stimulated transcription (using
0.5 µg of HIF-1) by as little as 0.1 µg of wtp53 in SKBr3 cells and
0.5 µg of wtp53 in PC3M cells (Fig. 1, A and
B).

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Fig. 1.
p53 represses HIF-1 stimulated transcription
from VEGF- and Epo- promoter constructs. A and B,
SKBr3 cells (A) or PC3M cells (B) were
transiently transfected with VEGF-Luc indicator plasmid only (0.5 µg,
lane 1), indicator plasmid + CMV.HA-HIF-1 (0.5 µg,
lanes 2-6), and additional plasmids as indicated:
lane 3, + wtp53 (0.1 µg); lane 4, + wtp53 (0.5 µg); lane 5, + wtp53 (2 µg); lane 6, + p53-273H (2 µg). Total amount of DNA transfected was maintained at
3.0 µg by equalizing each transfection with the appropriate amount of
pCMV. -galactosidase. Cells were lysed and assayed for luciferase
activity 36-40 h after transfection. Data are expressed as mean ± S.D. of at least three independent determinations. C,
PC3M cells were transfected and analyzed as indicated for A
and B, but 0.5 µg of pGL2-control replaced VEGF-Luc as the
indicator plasmid, and CMV.HA-HIF-1 was omitted. D, SKBr3
cells were transiently transfected with either the indicator plasmids
Epo-Luc (0.5 µg, lanes 1-3) or mutated Epo-Luc (mEpo-Luc,
0.5 µg, lanes 4-6), and CMV.HA-HIF-1 (0.5 µg,
lanes 1-6). Lanes 2 and 5 were
co-transfected with 2.0 µg of wtp53, whereas lanes 3 and
6 were co-transfected with 2.0 µg of p53-273H. Luciferase
activity was analyzed as in A and B.
|
|
The Transactivating Function of p53 Is Not Required for Suppression
of HIF-1
Activity--
In order to determine whether
transactivating capability was essential for p53-mediated HIF
inhibition, we next examined the HIF-1 inhibitory activity of the p53
"DNA contact" mutant p53-273H (16), which failed to transactivate
three independent p53-responsive reporters: PG13-Luc, WWP-Luc, and
Bax-Luc (data not shown). Although lacking transactivating capability,
p53-273H repressed HIF-1-driven transcription in both SKBr3 and PC3M
cells (Fig. 1, A, B, and D),
demonstrating that neither DNA binding nor transactivation is essential
for p53-mediated suppression of HIF-1 activity.
To confirm the specificity of this phenomenon, we tested the effects of
both wtp53 and p53-273H on a control luciferase plasmid, pGL2-control
(VEGF-Luc is a pGL2-based reporter and Epo-Luc is a pGL3-based
reporter), in transiently transfected PC3M cells. At the concentrations
used in these experiments, neither p53 construct significantly
inhibited the SV40-driven luciferase activity generated from
pGL2-control-transfected cells (Fig. 1C).
p53-mediated HIF Suppression Correlates with Stimulation of PARP
Cleavage but Not with the Transactivating Function of
p53--
Although p53-mediated suppression of HIF activity can be
clearly demonstrated, it requires higher p53 levels than are necessary to observe p53-mediated transactivation. Thus, transactivation of
PG13-Luc in SKBr3 cells requires co-transfection of 10-20-fold less
p53 than is necessary to obtain significant HIF-1 inhibition (Fig.
2A). Because transfection does
not introduce p53 into 100% of the cells tested, it is difficult to
compare suppression of HIF activity with the growth inhibitory and
apoptotic activity of p53. Since we demonstrated previously that
essentially 100% of cells infected with the p53-containing adenovirus
Ad-p53 express wtp53 protein following infection (minimum MOI = 2;
see Ref. 13), we used this approach to further explore the relationship
of p53 expression to transactivation and HIF suppression,
respectively.

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Fig. 2.
p53-stimulated suppression of HIF activity
correlates with PARP cleavage but not with p53-mediated transactivation
or growth arrest. A, comparison of the amounts of pCMV.wtp53
necessary to stimulate PG13-Luc and repress VEGF-Luc. SKBr3 cells were
transfected with PG13-Luc (0.5 µg, open circles) or
VEGF-Luc (0.5 µg) together with CMV.HA-HIF-1 (0.5 µg,
closed circles) and co-transfected with increasing amounts
of CMV.wtp53 as indicated on the x axis. Luciferase activity
was determined as in Fig. 1. Fold stimulation of PG13-Luc and fold
inhibition of VEGF-Luc are shown on the left and right
axes, respectively. B-F, SKBr3 cells were infected
with an increasing MOI of Ad-p53, and inhibition of Epo-Luc
(B), inhibition of DNA synthesis (C), stimulation
of PARP cleavage (D), induction of Mdm-2 protein
(E), and stimulation of Bax-Luc (F) were
determined. In each case, the first bar or gel
lane depicts uninfected cells, and the second bar or
lane (32*) depicts cells infected with 32 MOI of
Ad-LacZ. The numbers under the remaining bars (with
gel lanes corresponding) refer to the MOI of Ad-p53 used for
infection. In B, all cells were co-transfected with Epo-Luc
(0.5 µg) and CMV.HA-HIF-1 (0.5 µg). In F, all cells
were co-transfected with Bax-Luc (0.5 µg). In B and
F, transfections were performed 12-16 h prior to viral
infection, and assays were performed 24 h following viral
infection. In C-E, analyses were performed
24 h following viral infection.
|
|
We determined the MOI of Ad-p53 required in SKBr3 cells to yield
maximal inhibition of Epo-Luc (Fig. 2B) and DNA synthesis (Fig. 2C), stimulation of PARP cleavage (Fig.
2D), induction of Mdm-2 protein (Fig. 2E), and
stimulation of Bax-Luc (Fig. 2F). To control for any
nonspecific effects of viral titer, cells were infected with 32 MOI of
Ad-LacZ (second bar/lane in Fig. 2, B-F). PARP
cleavage is an early event in apoptosis, and inhibition of DNA
synthesis is a marker of growth arrest. The data demonstrate that
near-maximal inhibition of DNA synthesis, Mdm-2 induction, and
transactivation of Bax-Luc occur at an Ad-p53 MOI of 2-4. In contrast,
both significant inhibition of HIF-responsive transcription and
stimulation of PARP cleavage do not occur until an MOI of 16-32 is
reached. Infection with Ad-LacZ was consistently without effect. Thus,
whereas the transactivating function of p53 correlates with induction
of growth arrest, suppression of HIF activity correlates with the
higher amount of p53 required to initiate apoptosis. Similar to
what was found in the previous transfection experiment (Fig.
2A), 8-16-fold more p53 was needed to suppress HIF activity and stimulate PARP cleavage than was required to support
transactivation of p53 target genes and to cause growth arrest.
These results are in agreement with our earlier observation that
transactivation does not play a role in the inhibition of HIF activity
by p53. Taken together with our recent observation that p53
co-precipitates with HIF-1
(12), the data fit a model in which
direct association of HIF-1
with p53 results in HIF inhibition.
p53 Interaction with p300 Is Required for Inhibition of HIF
Activity--
Both HIF-1
and p53 bind to p300, and p300 is required
for full activity of both transactivators (17-21). Thus, it was of
interest to determine whether p300 plays any role in p53-mediated HIF
inhibition. We first determined whether exogenous p300 could restore
HIF activity in the presence of p53. We transfected PC3M cells with
Epo-Luc and HIF-1
, plus either CMV-
-galactosidase (control
plasmid) or wtp53, and full-length p300 (Fig.
3A). Although exogenous p300 augmented HIF-dependent transcriptional activity, as
reported previously (17), it could not reverse p53-mediated inhibition of this activity.

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Fig. 3.
p53 interaction with p300 is necessary for
repression of HIF-1 activity. A, PC3M cells were transfected
with Epo-Luc (0.5 µg) and CMV.HA-HIF-1 (0.5 µg) and
cotransfected with CMV. -galactosidase (0.2 µg, lanes 1,
3, and 5), CMV.wtp53 (0.2 µg, lanes
2, 4, and 6), pCMV.p300 (2.0 µg,
lanes 3-4), and pCMV.p300(1514-1922) (2.0 µg,
lanes 5-6). Luciferase activity and Mdm-2 protein levels
were determined after 36 h. For each pair of bars, the
value obtained in the absence of transfected p53 was set to 100%. In
the absence of p53, co-transfection of HIF-1 and full-length p300
augmented Epo-Luc activity an additional 5-fold compared with
transfection with HIF-1 alone, whereas Epo-Luc activity in cells
co-transfected with p300(1514-1922) and HIF-1 was 0.6-fold greater
than in cells transfected with HIF-1 alone. B, PC3M cells
were transfected with either wtp53 (0.25 µg) or the double point
mutant p53(22/23) (2 µg), together with Epo-Luc (0.5 µg) and
HA-HIF-1 (0.5 µg). Luciferase activity was determined after
36 h.
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|
HIF-1
and p53 bind to distinct regions of p300. The HIF binding site
has been localized to a region encompassed by amino acids 346-410
(17), whereas p53 has been reported to bind to a p300 fragment
comprising amino acids 1514-1922 (18, 21). These findings raise the
possibility that p53 and HIF-1
can bind to p300 simultaneously,
leading to interference by p53 in HIF/p300-mediated transactivation.
This model predicts that exogenous p300 would be unable to reverse
HIFsuppression as long as intracellular p53 levels exceed HIF levels.
Such a stoichiometric hypothesis can also explain why significantly
higher amounts of p53 are necessary to inhibit HIF than are required to
transactivate target genes and why p53 need not be transactivation
competent to mediate HIF suppression.
Based on this model, a p300 fragment that bound p53 but not HIF-1
would be expected to block p53-mediated HIF repression. To test this,
we repeated the above experiment but co-transfected with the
p53-binding p300 fragment, p300(1514-1922), instead of full-length
p300. Since it lacks the HIF-1
binding site this fragment did not
further stimulate HIF activity, but it markedly ameliorated
p53-mediated inhibition of this activity (Fig. 3A). Co-transfection of p300(1514-1922) did not affect the level of expression of p53 (not shown), but it did abrogate the ability of p53
to induce endogenous Mdm-2 (see Fig. 3A, inset),
previously shown to be dependent on p53/p300 interaction (21). These
data suggest that p300(1514-1922) reversed p53-mediated inhibition of
HIF-dependent transcription by sequestering p53 and
preventing its association with the endogenous pool of p300.
In order to further explore the requirement for p300 in p53-mediated
inhibition of HIF-1, we tested the anti-HIF activity of a p53 double
point mutant, p53(22/23), which is mutated at residues 22 and 23 in the
amino-terminal transactivating domain (5, 22) and does not bind to p300
(21). As can be seen in Fig. 3B, this mutant was unable to
suppress HIF-1 activity in PC3M cells. Although 0.25 µg
of wtp53 markedly inhibited HIF-1, p53(22/23) was inactive even when
transfected at 2 µg. Both wtp53 and p53(22/23) were expressed to
similar levels, as monitored by Western blotting (not shown). Taken
together, these data demonstrate that p53 must bind to p300 in order to
inhibit HIF-1.
Drug-induced Elevation of Endogenous wtp53 Suppresses HIF-1
Activity--
Although exogenously supplied p53 inhibits HIF-1-driven
transcription at levels that initiate apoptotic events, we wished to
determine whether endogenous p53 could be induced to display similar
activity. Thus, we transfected MCF7 cells, which contain wtp53, with
Epo-Luc and HIF-1
and examined the effect on reporter activity of
the DNA-damaging drug doxorubicin, a potent inducer of wtp53. Treatment
with doxorubicin led to marked elevation of p53 and significantly
blunted HIF transcriptional activity (Fig. 4). Co-transfection of a human papilloma
virus E6-expressing plasmid together with Epo-Luc and HIF-1
reversed
this inhibition (Fig. 4). In contrast, doxorubicin had no effect on
HIF-1 activity in p53-null PC3M cells (data not shown).

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Fig. 4.
Endogenous wtp53 can be induced to levels
that inhibit HIF activity. MCF7 cells were transfected with
Epo-Luc and HIF-1 (0.5 µg each) in the presence or absence of E6
(2.0 µg) as indicated. Treatment with 200 ng/ml doxorubicin was begun
24 h after transfection and continued for an additional 20 h,
at which time cells were lysed and Epo-Luc activity was determined
(A). The activity obtained in the absence of E6 and
doxorubicin was set at 100%. The relative increase in endogenous p53
steady-state protein level following doxorubicin is shown in
B.
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|
In summary, we have demonstrated that p53 is able to repress HIF
activity in a manner not requiring the transactivating function of p53.
That a significantly greater amount of p53 is necessary to inhibit HIF
than is required to transactivate p53 target genes or cause growth
arrest can be explained by a stoichiometric model in which p53 must
saturably bind to HIF/p300-containing complexes in order to inhibit
HIF. The physiologic relevance of this phenomenon is supported by two
observations. First, the level of p53, which must be reached to mediate
HIF repression, is equivalent to that at which PARP cleavage becomes
detectable, and second, this level of p53 can be reached in
vivo following exposure to a commonly used chemotherapeutic.
 |
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.
§
To whom correspondence should be addressed: Medicine Branch, Bldg.
10, Rm. 12N226, NCI, National Institutes of Health, Bethesda, MD 20892. Tel.: 301-496-6313; Fax: 301-402-0172; E-mail: mikhailb{at}box-m.nih.gov.
Current address: Dept. of Cell and Cancer Biology, Medicine
Branch, NCI, National Institutes of Health, Key West Facility, 9610 Medical Center Dr., Suite 300, Rockville, MD 20850.
1
The abbreviations used are: HIF-1
,
hypoxia-inducible factor-1
; VEGF, vascular endothelial growth
factor; Epo, erythropoietin; wtp53, wild type p53; MOI, multiplicity of
infection; Luc, luciferase; PARP, poly(ADP-ribose) polymerase; CMV,
cytomegalovirus.
 |
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