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Molecular Biology and Genetics |
1
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland 20892-4330 [A. S., S. M., V. P., M. Z., S. G.]; NIH-Howard Hughes Medical Institute Research Scholars Program, Bethesda, Maryland 20814 [A. S.] and Laboratory of Viral Oncogenesis, Division of Hematology-Oncology, Department of Medicine, Cornell University Medical College, New York, New York 10021 [C. B., E. A. M.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, which
activates transcription from a hypoxia response element within the
5'-flanking region of the VEGF promoter. Stimulation of HIF-1 by the
KSHV GPCR involves the phosphorylation of its regulatory/inhibitory
domain by the p38 and mitogen-activated protein kinase (MAPK) signaling
pathways, thereby enhancing its transcriptional activity. Moreover,
specific inhibitors of the p38 (SKF86002) and MAPK (PD98059) pathways
are able to inhibit the activation of the transactivating activity of
HIF-1 induced by the KSHV GPCR, as well as the VEGF expression and
secretion in cells overexpressing this receptor. These findings suggest
that the KSHV GPCR oncogene subverts convergent physiological pathways
leading to angiogenesis and provide the first insight into a mechanism
whereby growth factors and oncogenes acting upstream from MAPK, as well
as inflammatory cytokines and cellular stresses that activate p38, can
interact with the hypoxia-dependent machinery of angiogenesis. These
results may also help to identify novel targets for the development of
antiangiogenic therapies aimed at the treatment of Kaposi’s sarcoma
and other neoplastic diseases. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The complexity of the mechanism controlling VEGF expression has just
begun to be appreciated. For example, tissue hypoxia and exposure to
compounds that mimic cellular hypoxia, such as cobalt ions, can induce
a remarkable increase in VEGF expression (8)
by enhancing
the stability (9
, 10)
and transcriptional activity
(11)
of HIF-1 and by prolonging the half-life of VEGF
transcripts (12)
. VEGF expression is also potently
stimulated under normoxic conditions by growth factors and cellular
stresses; by a variety of cytokines, such as IL-1, tumor necrosis
factor , and IL-8; and by tumorigenic genes, including
ras, raf, and src (6
, 7
, 13, 14, 15)
. Recent efforts are now helping to unveil the nature of
the signaling pathways linking these oncogenes with the transcription
factor HIF-1 (16, 17, 18)
.
Of interest, KS, the most common AIDS-associated neoplasm, is a neovascular tumor that has been shown to be strictly dependent on angiogenic stimulators, including VEGF (19 , 20) . For example, spindle cells, the dominant cell type of KS lesions, secrete a variety of proinflammatory and angiogenic factors (19 , 20) , among which VEGF is unique for its extensive impact on KS pathogenesis: it is expressed at elevated levels by KS spindle cells and is suggested to stimulate their growth by an autocrine mechanism (20) . Compelling evidence points to KSHV or human herpes virus 8 as the infectious etiological agent of KS (21) : (a) KSHV infection precedes KS development and overlaps with KS risks (22 , 23) ; (b) KSHV infects KS spindle and endothelial cells in the KS lesion (23) ; and (c) KSHV infects and transforms cells thought to be premalignant for KS (24) . Because KSHV is highly homologous to two viruses implicated in malignancies, EBV and Herpesvirus saimiri, it is likely that KSHV is an oncogenic virus involved in the pathogenesis of KS. Indeed, molecular characterization of the KSHV genome has shown the existence of several genes that bear potential for KS pathogenesis (22 , 23) . These include genes that could lead to KS angiogenesis by inducing an angiogenic phenotype in KSHV-infected cells or by promoting inflammation or the production of angiogenesis-activating inflammatory cytokines (23 , 25, 26, 27) .
One of these KSHV angiogenic genes, encoded by the open reading frame 74, is a constitutively active CXC chemokine GPCR (KSHV GPCR), which is a close homologue of the one of the receptors, CXCR2, for the human angiogenic chemokine IL-8 (28 , 29) . KSHV GPCR contains a V138D mutation in the highly conserved DRY sequence among the GPCRs, which results in an increased agonist-independent receptor activity (29) . Indeed, this KSHV GPCR harbors transforming and angiogenic potential and is sufficient to induce the secretion of VEGF from KSHV GPCR-expressing cells (25) . Furthermore, expression of KSHV GPCR in transgenic mice leads to the occurrence of KS-like lesions with VEGF-driven angiogenesis and spindle cell proliferation (30 , 31) . These findings suggest that KSHV GPCR might participate in KS pathogenesis, driving spindle cell formation, growth, and angiogenesis in a paracrine fashion by inducing the expression and secretion of VEGF (25 , 30 , 31) .
The complexity of the signal transduction routes initiated by GPCRs has begun to be unraveled (32, 33, 34) . In this study, we have investigated the intracellular pathways controlling VEGF expression by the KSHV GPCR. These observations could provide a unique opportunity to help elucidate the still poorly understood molecular mechanism(s) whereby viral and cellular oncogenes regulate the expression and secretion of VEGF and, ultimately, govern tumor-induced angiogenesis.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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pBS KS-HIF-1, obtained from American Type Culture Collection (EST
22495), was subcloned into the pCEFL vector as a
BamHI-XbaI fragment, thus generating the pCEFL
HIF-1 expression plasmid. pALTER-1 HIF-1ß, generously provided by
E. Bradfield (Northwestern University Medical School, Chicago,
IL), was subcloned into the pCEFL vector as a
HindIII-XbaI fragment, thus generating the pCEFL
HIF-1ß expression plasmid. The TADs of HIF-1 (amino acids
531–826; Ref. 36
) and Elk-1 (amino acids 307–428; Ref.
37
) transcription factors were expressed as GAL4
fusion proteins after amplification of the corresponding DNA sequences
and subcloning in frame within a pcDNA III derivative expressing the
DNA binding domain of the yeast transcription factor GAL4 (amino acids
1–147). The pGL3.TATA GAL-driven luciferase reporter plasmid was
constructed as described previously (38)
. The GST-HIF-1
fusion protein carrying amino acids 568–702 of the HID was obtained by
PCR using human HIF-1 cDNA as a template. The fragment was then
subcloned between the BamHI and EcoRI site of
pGEX4T-3 (Pharmacia), in frame with the GST gene.
Sequences of oligonucleotide primers will be provided on request. Other
expression plasmids have already been described (38
, 39)
.
Cell Lines and Transfection.
Stable transfections of NIH 3T3 cells were performed using
LipofectAMINE Plus reagent (Life Technologies, Inc.) according to the
manufacturer’s protocol. NIH 3T3 fibroblasts stably expressing the
KSHV GPCR or GFP, designated NIH-KS.GPCR or NIH-GFP, respectively, were
maintained as described previously (25)
. For transient
transfections for reporter gene assays, NIH 3T3 cells and MDCK cells
were transfected by using the calcium-phosphate precipitation
technique. COS-7 cells were transfected by the DEAE-dextran method. In
each experiment, the total amount of DNA was adjusted to 3–5
µg/plate using pCEFL GFP.
Northern Blot Analysis.
Total RNA was isolated from NIH-KS.GPCR or NIH-pCEFL using Trizol (Life
Technologies, Inc.) according to the manufacturer’s instructions,
separated by electrophoresis on a 2% denaturing glyoxal-DMSO gel
(10 mg RNA/lane), and transferred to a Nytran-N nylon membrane
(Schleicher & Schuell). The cDNA probe used for analysis of the VEGF
and ß-actin mRNA was prepared using reverse transcription-PCR
products obtained from mouse total RNA as a template. Probes were
labeled with [-32P]dCTP using a Random
Primer DNA labeling kit (Boehringer Mannheim), and RNA hybridization
was performed as described previously (39)
.
Reporter Gene Assays.
NIH-KS.GPCR, NIH-GFP, and MDCK cells were transfected with the
different expression plasmids together with 0.5 µg of
pcDNAIII-ßgal, a plasmid expressing the enzyme ß-galactosidase, and
0.25 µg of either pGL-VEGF/K, pGL-VEGF/P, pGL-HRE, or pGL-HREmut,
reporter plasmids expressing the luciferase gene under the control of
the VEGF promoter or a HRE. After overnight incubation, cells were
washed once with PBS and kept for approximately 36 h in DMEM
supplemented with 10% calf serum (NIH 3T3 cells) or FCS (MDCK
cells). Cells were then lysed using reporter lysis buffer
(Promega). Luciferase activity and ß-galactosidase activity present
in cellular lysates were assayed as described previously
(38)
. The data for luciferase activity, normalized by the
ß-galactosidase activity, are expressed as the fold induction with
respect to control cells and are the mean ± SE of
triplicate samples from a typical experiment.
COS-7 cells were transfected with different expression plasmids together with 0.5 µg of pcDNAIII-ßgal, 0.5 µg of pGL3.TATA GAL, and 0.5 µg of the pcDNAIII GAL4/HIF expression plasmid. After overnight incubation, COS-7 cells were washed once with PBS and kept for approximately 36 h in DMEM supplemented with 10% FCS. Cells were then lysed using reporter lysis buffer (Promega). Additional DNAs were added to the transfection mixtures as indicated in each figure. Luciferase activity and normalization for transfection efficiency were done as described above.
Kinase Assays.
The phosphorylating activity of epitope-tagged MAPK, JNK p38,
p38
, and p38
was assayed as described previously
(38)
. In vitro kinase assays were performed
using either 5 µg of myelin basic protein (Sigma; for MAPK, p38,
and p38), 5 µg of purified bacterially expressed GST-ATF2 (for JNK
and p38), or 5 µg of purified, bacterially expressed GST-HID as
substrates. Samples were analyzed by SDS-gel electrophoresis on
12% acrylamide gels, and autoradiography was performed with the aid of
an intensifying screen. GST-fusion proteins were expressed in bacteria
and purified by affinity chromatography using standard procedures.
Western Blot.
HA immunoprecipitates from transiently transfected COS-7 cells carrying
HA-MAPK, JNK, extracellular signal-regulated kinase 5, p38, p38,
and p38 DNAs were analyzed by Western blotting after
SDS-polyacrylamide gel electrophoresis using an anti-HA
monoclonal antibody as described previously (38)
.
Kinase Inhibitors.
The p38 inhibitor (SKF86002) and the MEK inhibitor (PD98059;
Calbiochem, Inc.) were dissolved in DMSO as 1000-fold concentrated
stock solutions and used at the indicated concentrations. Cells were
then treated with either four doses of SKF86002 (one every 3 h for
12 h) or a single dose of PD98059 (for 8 h) before lysis. In
each case, the final concentration of DMSO was <0.1%.
ELISA.
Conditioned media from either NIH-KS.GPCR cells or NIH-GFP cells were
collected after 24 h. VEGF secretion was detected in the media
using a VEGF immunoassay kit (R&D Laboratories) as indicated in the
standard protocol provided by the manufacturer.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, these cells exhibit remarkably increased levels of VEGF
mRNA when compared with control cells expressing the empty pCEFL vector
(NIH-pCEFL). Similar high levels of VEGF mRNA could be observed in
cells transformed by the KSHV GPCR on prolonged culture, as well as in
tumors arising from NIH-KS.GPCR cells injected into nude mice
(25)
. To explore whether this enhanced steady-state level
of VEGF mRNA results from an increase in VEGF transcription, we
transfected NIH-KS.GPCR cells with pGL-VEGF/K, a reporter plasmid
expressing luciferase under the control of the full-length VEGF
promoter (35)
. As shown in Fig. 1B
, the VEGF
promoter was highly active in NIH-KS.GPCR cells, similar to that of
control cells exposed to hypoxia or CoCl2, which
mimics hypoxia (40)
. Furthermore, we observed a
synergistic increase in expression from the VEGF promoter when plasmids
for the transcriptional enhancers HIF-1 and HIF-1ß were
cotransfected into these cells (Fig. 1B)
, thus indicating
that the KSHV GPCR, as well as hypoxia (35)
, can
activate HIF-1 to stimulate the VEGF promoter.
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, in
these cells, both CoCl2 and the KSHV GPCR induced
transcription from the VEGF promoter effectively. However, the
stimulation by the KSHV GPCR and CoCl2 was
markedly reduced when we used a truncated VEGF reporter construct
lacking the HRE, pGL-VEGF/P, suggesting that the ability of the KSHV
GPCR to stimulate expression from the VEGF promoter requires an intact
HRE. We next asked whether the KSHV GPCR could activate transcription
from an isolated HRE. For these experiments, we engineered a reporter
plasmid expressing the luciferase gene under the control of a single
VEGF HRE consensus sequence, which was designated pGL-HRE. As shown in
Fig. 1D
, the viral-encoded GPCR strongly induced the pGL-HRE
to a level similar to that achieved by CoCl2
treatment. However, both KSHV GPCR and CoCl2
failed to stimulate a control reporter plasmid, pGL-HREmut, which is
identical to pGL-HRE but contains a mutation in the HIF-1 binding site
(35)
, supporting the specificity of the transcriptional
response. Taken together, these results indicate that the KSHV GPCR can
stimulate expression from the VEGF promoter by activating transcription
from a HRE.
The KSHV GPCR Induces the MEK/MAPK and MKK6/p38 Signaling Pathways:
A Potential Role in the Activation of the VEGF Promoter.
Because the KSHV GPCR was able to stimulate the activity of the VEGF
promoter through its HRE, we next sought to investigate the nature of
the biochemical pathways linking this viral GPCR to HIF-1. We focused
our attention on the MAPK superfamily of proline-directed
serine-threonine kinases because they are central components of many
signaling routes communicating cell surface receptors to the nucleus
(32, 33, 34)
. To determine which such kinase pathways might be
stimulated by the KSHV GPCR in our cellular system, we screened
representative members of each MAPK family for enhanced activity in the
presence of cotransfected KSHV GPCR. The expression of this receptor
was able to enhance the activity of MAPK, p38, p38, and p38
but had a more limited effect on JNK (Fig. 2A)
. We then explored whether any of these MAPK pathways could
stimulate the activity of the VEGF promoter, taking advantage of the
availability of activated molecules acting upstream from each of the
MAPK cascades, including MEK, which activates MAPK (41)
,
MKK6, which activates p38, p38, and p38 (37)
, and
MEKK1, which activates JNK (42)
. As shown in Fig. 2B
, expression of activated mutants of both MEK and MKK6,
but not of MEKK1, provoked a potent induction of the pGL-VEGF/K
reporter plasmid. Interestingly, induction of the truncated pGL-VEGF/P,
which lacks the HRE, by these kinases was greatly diminished, thus
suggesting a role for HIF-1 in both MEK and MKK6 stimulation of
transcription from the VEGF promoter. Furthermore, the activated forms
of both MEK and MKK6 also strongly induced the HRE reporter plasmid,
pGL-HRE, but showed no induction of the pGL-HREmut (Fig. 2C)
. These data indicated that both MEK and MKK6 and their
downstream MAPKs can induce HIF-1-dependent transcription from the VEGF
promoter.
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in Its
Regulatory/Inhibitory Domain and Enhance Its Transcriptional Activity./HIF-1ß heterodimer, the HIF-1 subunit has been
shown to be the essential element for the hypoxic regulation of the HRE
(11)
, whereas HIF-1ß, although unaffected by hypoxia,
appears to be required for DNA binding. HIF-1 contains a DNA binding
domain (amino acids 1–390) that includes the heterodimerization domain
(amino acids 1–166) and a TAD (amino acids 531–826). This last domain
includes a negative regulatory region (amino acids 575–786) that
inhibits the transcriptional activity of the adjacent
NH2-terminal and COOH-terminal transactivating
regions under normoxic conditions (see Fig. 3
A, N-TAD and C-TAD; Ref. 36
). Within
this inhibitory domain, there are eight serine residues that may be
putative targets for members of the MAPK superfamily. To explore
whether kinase-induced HIF-1-dependent transcription was mediated by
activation of HIF-1 through phosphorylation, we constructed a fusion
protein containing the NH2-terminal domain of GST
and the HID. As shown in Fig. 3B
, activated MAPK, p38,
and p38 were able to phosphorylate the GST-HID fusion protein but
not the GST protein alone. Activated p38 and JNK, however, were
unable to use the GST-HID as a substrate, although both were able to
phosphorylate GST-ATF2 when used as a control. These data suggest that
HIF-1 can be a direct target for phosphorylation by MAPK, p38,
and p38, thus providing a possible mechanism for the induction of
HIF-1-dependent transcription by MEK and MKK6.
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TAD, we constructed a chimeric
GAL4-core HIF-1 fusion molecule (Gal4/HIF) containing both the
NH2-terminal and COOH-terminal TADs and the
regulatory/inhibitory domain (Fig. 3C
; Ref.
36
). This GAL4/HIF chimera was found to be stable and
localized to the nucleus under normoxic conditions (data not shown),
thus permitting the investigation of HIF-1 transactivation activity
independently of other mechanisms affecting protein stability and
nuclear localization. We then expressed activated mutants of MEK, MKK6,
and MEKK1 together with GAL4/HIF and the pGL3-TATA GAL reporter
plasmid. As shown in Fig. 3C
, both the activated mutants of
MEK and MKK6 potently induced the transcriptional activity of GAL4/HIF.
Additional molecules acting upstream of MAPK, such as Raf and Ras, were
also able to potently stimulate the activity of the GAL4/HIF chimera
(data not shown). In contrast, the activated mutant of MEKK1 had little
effect on GAL4/HIF, although it effectively activated a GAL4/Elk-1
fusion construct when used as control (Fig. 3C)
. Thus, these
data indicate that signaling routes activating MAPK, p38, and p38
can stimulate the transcriptional activity of HIF1- by direct
phosphorylation of its regulatory domain.
p38 and MAPK Signaling Pathways Mediate the Stimulating Effects of
the KSHV GPCR on the Transactivating Activity of HIF-1.
To examine whether the KSHV GPCR could also act through the HIF-1
transactivating domain, we investigated the effect of transiently
expressing increasing amounts of KSHV GPCR cDNA on the activity of the
GAL4/HIF chimera, cotransfecting the corresponding DNAs along with the
pGL3.TATA GAL reporter plasmid. As shown in Fig. 4A
, the KSHV GPCR was able to induce the transcriptional
activity of GAL/HIF in a dose-dependent manner but had little effect on
the GAL4 protein alone. To further elucidate the biochemical route used
by this viral receptor to activate HIF-1, we took advantage of the
availability of pharmacological agents that specifically block either
the p38 (SKF86002) or MAPK (PD98059) pathways (45
, 46)
.
Thus, we studied the KSHV GPCR-mediated induction of GAL4/HIF
transcriptional activity in the presence of increasing concentrations
of either compound. Fig. 4, B and C
, shows a
clear dose-dependent inhibition of KSHV GPCR activation of GAL4/HIF
when cells were treated with either SKF86002 or PD98059, respectively.
However, these compounds did not affect GAL4/Elk-1 activation by MEKK1
when used as a control. These data suggest that the KSHV GPCR enhances
the transcriptional activity of HIF-1 through the p38 and MAPK
signal transduction pathways.
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, shows the percentage of inhibition of
transcription from the VEGF promoter (pGL-VEGF/K) in response to
increasing concentrations of SKF86002 or PD98059, with respect to
control-treated cells. Both kinase inhibitors reduced transcription
from the full-length VEGF promoter in NIH-KS.GPCR cells in a
dose-dependent manner. Moreover, the inhibition of the VEGF promoter
activity affected the KSHV GPCR-induced VEGF secretion, as the
treatment with SKF86002 or PD98059 also decreased the levels of VEGF
secreted from NIH-KS.GPCR cells. As shown in Fig. 5, A and B
, a clear dose-dependent inhibition of VEGF secretion by
SKF86002 or PD98059 was observed in NIH-KS.GPCR cells, paralleling the
effects of these kinase inhibitors on the VEGF promoter activity. To
further control for the specificity of the pharmacological inhibitors,
we ran a parallel control experiment showing that VEGF transcription
and secretion by NIH 3T3 cells transformed by RasV12, an oncogene that
activates MAPK and fails to activate p38, were inhibited by PD98059 but
not by SKF86002 (data not shown). Taken together, these data strongly
suggest that the KSHV GPCR induces the expression and secretion of VEGF
by stimulating the activity of the VEGF promoter through the p38 and
MAPK signaling pathways, acting on the transactivating domain of
HIF-1.
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DISCUSSION |
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Here we show that the KSHV GPCR induces expression of VEGF by
stimulating transcription from a HRE, which binds the HIF-1/HIF-1ß
heterodimer, within the 5'-flanking region of the VEGF promoter
(11)
. We found that the KSHV GPCR could directly stimulate
the transcriptional activity of HIF-1 using a GAL4-core HIF-1
fusion protein that contains both NH2- and
COOH-terminal TADs of HIF-1 and a HID domain that inhibits the
activity of these transactivating regions. Furthermore, we
provide evidence that the activation of HIF-1 may involve the direct
phosphorylation of this transcription factor by the p38 and MAPK
signaling pathways within the HID domain (amino acids 575–786).
Finally, we also demonstrate that specific inhibitors of the p38 and
MAPK pathways (SKF86002 and PD98059) are able to diminish the
expression and secretion of VEGF induced by the KSHV GPCR, indicating
that these pathways are necessary and sufficient for the viral receptor
to stimulate transcription from the VEGF promoter. These results
indicate that this viral oncogene is able, under normoxic conditions,
to subvert the hypoxia response pathway, which is the strongest
physiological regulator of VEGF expression.
These findings may have a broad impact on our understanding of the
pathophysiological mechanisms involved in the acquisition of the
angiogenic phenotype. Our results showing that KSHV GPCR activates
HIF-1-mediated transcription of the VEGF gene via MAPK and p38 under
normoxic conditions point to a general mechanism explaining how
oncogenes and inflammation up-regulate VEGF and could synergize with
hypoxia in tumors. Indeed, expression and secretion of VEGF are also
induced by activated oncogenes such as ras, raf,
and src (14
, 15)
, which activate MAPK, and by
cytokines and chemokines such as IL-1, tumor necrosis factor , and
IL-8 (7
, 13)
, which stimulate p38 (47
, 48)
.
Furthermore, these observations are also in line with recently
published reports implicating the MAPK signaling pathway in increasing
the transcriptional activity of HIF-1 independent of its protein
stability (16)
. Of interest, the KSHV-GPCR may also
regulate the stability of HIF-1, for example, through the Akt
pathway as reported for other oncogenes (17
, 18)
, a
possibility that is currently under investigation.
Using the KSHV GPCR as a model system for oncogenic and
cytokine-induced VEGF secretion, we are now able to state that
at least two distinct signaling pathways regulate the transactivating
activity of the transcriptional enhancer HIF-1. As depicted in Fig. 6
, this novel mechanism, together with those described previously such as
increased half-life of HIF-1 (9)
and stabilization of
VEGF mRNA (12)
, may ultimately control VEGF secretion and
thus play a critical role in angiogenesis, in normal physiological
situations as well as in neoplastic diseases. Interestingly, the
inhibition of angiogenesis is considered one of the most promising
strategies for the development of novel antineoplastic therapies
because targeting of the tumor vasculature might have minimal side
effects even after prolonged treatment and should not lead to the
development of resistance (49)
. Because systemic
chemotherapy treatment for advanced disseminated forms of KS has been
shown to be extremely difficult to tolerate, not only in AIDS patients
but also in patients with other clinical varieties of this neoplasm
(50)
, the development of rational or pathogenesis-based
therapies might provide useful alternatives or additions to the use of
cytotoxic drugs (50)
. In this regard, antiangiogenic
therapies have shown promising results in the treatment of KS
(51, 52, 53)
. Thus, our findings establishing a
molecular mechanism whereby the KSHV GPCR stimulates the expression and
secretion of VEGF might help to identify novel therapeutic targets for
KS and other neoplastic and angioproliferative diseases.
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FOOTNOTES |
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1 Supported in part by NIH Grant AI-39192 and
Research Project Grant RPG-99-207-01-MBC from the American Cancer
Society (to E. A. M.). A. S. is supported by a predoctoral
fellowship from the NIH-Howard Hughes Medical Institute Research
Scholars Program. S. M. is supported by a fellowship from the
Fundacion Ramon Areces. 
2 To whom requests for reprints should be
addressed, at Oral and Pharyngeal Cancer Branch, National Institute of
Dental and Craniofacial Research, NIH, 30 Convent Drive, Building 30,
Room 211, Bethesda, MD 20892-4330. Phone: (301) 496-6259; Fax: (301)
402-0823; E-mail: SG39v{at}nih.gov
3 The abbreviations used are: VEGF, vascular
endothelial growth factor; KS, Kaposi’s sarcoma; KSHV, Kaposi’s
sarcoma-associated herpes virus; GPCR, G protein-coupled receptor;
MAPK, mitogen-activated protein kinase; HIF, hypoxia-inducible factor;
HRE, hypoxia response element; IL, interleukin; GST, glutathione
S-transferase; GFP, green fluorescence protein; MDCK,
Madin-Darby canine kidney; JNK, c-Jun-NH2-terminal kinase;
MEK, mitogen-activated protein/extracellular signal-regulated kinase;
MKK6, MAP kinase kinase 6; MEKK1, MAP, kinase kinase kinase
1; TAD, transactivation domain; HID, HIF-1
regulatory/inhibitory domain; ATF2, activating transcription factor 2;
HA, hemagglutinin.
Received 1/13/00. Accepted 7/ 5/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc. Natl. Acad. Sci. USA, 95: 7987-7992, 1998. stimulate DNA binding of hypoxia-inducible factor-1. Blood, 94: 1561-1567, 1999. (HIF-1) and enhance the transcriptional activity of HIF-1. J. Biol. Chem., 274: 32631-32637, 1999. expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res., 60: 1541-1545, 2000. subunit. J. Biol. Chem., 272: 11205-11214, 1997.. Modulation of transcriptional activity by oxygen tension. J. Biol. Chem., 272: 19253-19260, 1997.This article has been cited by other articles:
|
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 |
|
  D. Maussang, H. F. Vischer, R. Leurs, and M. J. Smit Herpesvirus-Encoded G Protein-Coupled Receptors as Modulators of Cellular Function Mol. Pharmacol., October 1, 2009; 76(4): 692 - 701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Jin, X. An, Z. Ye, B. Cully, J. Wu, and J. Li RGS5, a Hypoxia-inducible Apoptotic Stimulator in Endothelial Cells J. Biol. Chem., August 28, 2009; 284(35): 23436 - 23443. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-P. Couty, M. Lupu-Meiri, Y. Oron, and M. C. Gershengorn Kaposi's Sarcoma-Associated Herpesvirus-G Protein-Coupled Receptor-Expressing Endothelial Cells Exhibit Reduced Migration and Stimulated Chemotaxis by Chemokine Inverse Agonists J. Pharmacol. Exp. Ther., June 1, 2009; 329(3): 1142 - 1147. [Abstract] [Full Text] [PDF]
|
|
|
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D. Martin, R. Galisteo, and J. S. Gutkind CXCL8/IL8 Stimulates Vascular Endothelial Growth Factor (VEGF) Expression and the Autocrine Activation of VEGFR2 in Endothelial Cells by Activating NF{kappa}B through the CBM (Carma3/Bcl10/Malt1) Complex J. Biol. Chem., March 6, 2009; 284(10): 6038 - 6042. [Abstract] [Full Text] [PDF]
|
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|
 |
|
 Y. C. Shin, C.-H. Joo, M. U. Gack, H.-R. Lee, and J. U. Jung Kaposi's Sarcoma-Associated Herpesvirus Viral IFN Regulatory Factor 3 Stabilizes Hypoxia-Inducible Factor-1{alpha} to Induce Vascular Endothelial Growth Factor Expression Cancer Res., March 15, 2008; 68(6): 1751 - 1759. [Abstract] [Full Text] [PDF]
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|
 Y. Ding, E. A. Boguslawski, B. D. Berghuis, J. J. Young, Z. Zhang, K. Hardy, K. Furge, E. Kort, A. E. Frankel, R. V. Hay, et al. Mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma Mol. Cancer Ther., March 1, 2008; 7(3): 648 - 658. [Abstract] [Full Text] [PDF]
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 R. Sivakumar, N. Sharma-Walia, H. Raghu, M. V. Veettil, S. Sadagopan, V. Bottero, L. Varga, R. Levine, and B. Chandran Kaposi's Sarcoma-Associated Herpesvirus Induces Sustained Levels of Vascular Endothelial Growth Factors A and C Early during In Vitro Infection of Human Microvascular Dermal Endothelial Cells: Biological Implications J. Virol., February 15, 2008; 82(4): 1759 - 1776. [Abstract] [Full Text] [PDF]
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E. Kuang, Q. Tang, G. G. Maul, and F. Zhu Activation of p90 Ribosomal S6 Kinase by ORF45 of Kaposi's Sarcoma-Associated Herpesvirus and Its Role in Viral Lytic Replication J. Virol., February 15, 2008; 82(4): 1838 - 1850. [Abstract] [Full Text] [PDF]
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D. Huang, Y. Ding, W.-M. Luo, S. Bender, C.-N. Qian, E. Kort, Z.-F. Zhang, K. VandenBeldt, N. S. Duesbery, J. H. Resau, et al. Inhibition of MAPK Kinase Signaling Pathways Suppressed Renal Cell Carcinoma Growth and Angiogenesis In vivo Cancer Res., January 1, 2008; 68(1): 81 - 88. [Abstract] [Full Text] [PDF]
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 |
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 R. F. Little, K. Aleman, P. Kumar, K. M. Wyvill, J. M. Pluda, E. Read-Connole, V. Wang, S. Pittaluga, A. T. Catanzaro, S. M. Steinberg, et al. Phase 2 study of pegylated liposomal doxorubicin in combination with interleukin-12 for AIDS-related Kaposi sarcoma Blood, December 15, 2007; 110(13): 4165 - 4171. [Abstract] [Full Text] [PDF]
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M. J. Martin, T. Tanos, A. B. Garcia, D. Martin, J. S. Gutkind, O. A. Coso, and M. J. Marinissen The G{alpha}12/13 Family of Heterotrimeric G Proteins and the Small GTPase RhoA Link the Kaposi Sarcoma-associated Herpes Virus G Protein-coupled Receptor to Heme Oxygenase-1 Expression and Tumorigenesis J. Biol. Chem., November 23, 2007; 282(47): 34510 - 34524. [Abstract] [Full Text] [PDF]
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|
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 |
|
 P. Depeille, J. J. Young, E. A. Boguslawski, B. D. Berghuis, E. J. Kort, J. H. Resau, A. E. Frankel, and N. S. Duesbery Anthrax Lethal Toxin Inhibits Growth of and Vascular Endothelial Growth Factor Release from Endothelial Cells Expressing the Human Herpes Virus 8 Viral G Protein Coupled Receptor Clin. Cancer Res., October 1, 2007; 13(19): 5926 - 5934. [Abstract] [Full Text] [PDF]
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 |
|
 H. W. J. Young, O. W. Williams, D. Chandra, L. K. Bellinghausen, G. Perez, A. Suarez, M. J. Tuvim, M. G. Roy, S. N. Alexander, S. J. Moghaddam, et al. Central Role of Muc5ac Expression in Mucous Metaplasia and Its Regulation by Conserved 5' Elements Am. J. Respir. Cell Mol. Biol., September 1, 2007; 37(3): 273 - 290. [Abstract] [Full Text] [PDF]
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 |
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 M.-C. Lauzier, E. L. Page, M. D. Michaud, and D. E. Richard Differential Regulation of Hypoxia-Inducible Factor-1 through Receptor Tyrosine Kinase Transactivation in Vascular Smooth Muscle Cells Endocrinology, August 1, 2007; 148(8): 4023 - 4031. [Abstract] [Full Text] [PDF]
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F.-C. Ye, D. J. Blackbourn, M. Mengel, J.-P. Xie, L.-W. Qian, W. Greene, I-T. Yeh, D. Graham, and S.-J. Gao Kaposi's Sarcoma-Associated Herpesvirus Promotes Angiogenesis by Inducing Angiopoietin-2 Expression via AP-1 and Ets1 J. Virol., April 15, 2007; 81(8): 3980 - 3991. [Abstract] [Full Text] [PDF]
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 |
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 D. P. Schuster, S. L. Brody, Z. Zhou, M. Bernstein, R. Arch, D. Link, and M. Mueckler Regulation of lipopolysaccharide-induced increases in neutrophil glucose uptake Am J Physiol Lung Cell Mol Physiol, April 1, 2007; 292(4): L845 - L851. [Abstract] [Full Text] [PDF]
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M. M. Brinkmann, M. Pietrek, O. Dittrich-Breiholz, M. Kracht, and T. F. Schulz Modulation of Host Gene Expression by the K15 Protein of Kaposi's Sarcoma-Associated Herpesvirus J. Virol., January 1, 2007; 81(1): 42 - 58. [Abstract] [Full Text] [PDF]
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I. Mylonis, G. Chachami, M. Samiotaki, G. Panayotou, E. Paraskeva, A. Kalousi, E. Georgatsou, S. Bonanou, and G. Simos Identification of MAPK Phosphorylation Sites and Their Role in the Localization and Activity of Hypoxia-inducible Factor-1{alpha} J. Biol. Chem., November 3, 2006; 281(44): 33095 - 33106. [Abstract] [Full Text] [PDF]
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|
P. A. Carroll, H. L. Kenerson, R. S. Yeung, and M. Lagunoff Latent Kaposi's Sarcoma-Associated Herpesvirus Infection of Endothelial Cells Activates Hypoxia-Induced Factors J. Virol., November 1, 2006; 80(21): 10802 - 10812. [Abstract] [Full Text] [PDF]
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Q. Ke and M. Costa Hypoxia-Inducible Factor-1 (HIF-1) Mol. Pharmacol., November 1, 2006; 70(5): 1469 - 1480. [Abstract] [Full Text] [PDF]
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S. Kondo, S. Y. Seo, T. Yoshizaki, N. Wakisaka, M. Furukawa, I. Joab, K. L. Jang, and J. S. Pagano EBV Latent Membrane Protein 1 Up-regulates Hypoxia-Inducible Factor 1{alpha} through Siah1-Mediated Down-regulation of Prolyl Hydroxylases 1 and 3 in Nasopharyngeal Epithelial Cells. Cancer Res., October 15, 2006; 66(20): 9870 - 9877. [Abstract] [Full Text] [PDF]
|
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|
|
T. K. Lee, R. T.P. Poon, A. P. Yuen, K. Man, Z. F. Yang, X. Y. Guan, and S. T. Fan Rac Activation Is Associated with Hepatocellular Carcinoma Metastasis by Up-regulation of Vascular Endothelial Growth Factor Expression Clin. Cancer Res., September 1, 2006; 12(17): 5082 - 5089. [Abstract] [Full Text] [PDF]
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S.-B. Catrina, I. R. Botusan, A. Rantanen, A. I. Catrina, P. Pyakurel, O. Savu, M. Axelson, P. Biberfeld, L. Poellinger, and K. Brismar Hypoxia-Inducible Factor-1{alpha} and Hypoxia-Inducible Factor-2{alpha} Are Expressed in Kaposi Sarcoma and Modulated by Insulin-like Growth Factor-I Clin. Cancer Res., August 1, 2006; 12(15): 4506 - 4514. [Abstract] [Full Text] [PDF]
|
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|
|
R. F. Little, J. M. Pluda, K. M. Wyvill, I. R. Rodriguez-Chavez, G. Tosato, A. T. Catanzaro, S. M. Steinberg, and R. Yarchoan Activity of subcutaneous interleukin-12 in AIDS-related Kaposi sarcoma Blood, June 15, 2006; 107(12): 4650 - 4657. [Abstract] [Full Text] [PDF]
|
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|
 |
|
 E. E. Brown, D. Fallin, I. Ruczinski, A. Hutchinson, B. Staats, F. Vitale, C. Lauria, D. Serraino, G. Rezza, G. Mbisa, et al. Associations of Classic Kaposi Sarcoma with Common Variants in Genes that Modulate Host Immunity. Cancer Epidemiol. Biomarkers Prev., May 1, 2006; 15(5): 926 - 934. [Abstract] [Full Text] [PDF]
|
|
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M. J. Marinissen, T. Tanos, M. Bolos, M. R. de Sagarra, O. A. Coso, and A. Cuadrado Inhibition of Heme Oxygenase-1 Interferes with the Transforming Activity of the Kaposi Sarcoma Herpesvirusencoded G Protein-coupled Receptor J. Biol. Chem., April 21, 2006; 281(16): 11332 - 11346. [Abstract] [Full Text] [PDF]
|
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|
|
 |
|
 A. Cohen, C. Brodie, and R. Sarid An essential role of ERK signalling in TPA-induced reactivation of Kaposi's sarcoma-associated herpesvirus. J. Gen. Virol., April 1, 2006; 87(Pt 4): 795 - 802. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Montaner, A. Sodhi, A. K. Ramsdell, D. Martin, J. Hu, E. T. Sawai, and J. S. Gutkind The Kaposi's Sarcoma-Associated Herpesvirus G Protein-Coupled Receptor as a Therapeutic Target for the Treatment of Kaposi's Sarcoma Cancer Res., January 1, 2006; 66(1): 168 - 174. [Abstract] [Full Text] [PDF]
|
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M. Cannon, E. Cesarman, and C. Boshoff KSHV G protein-coupled receptor inhibits lytic gene transcription in primary-effusion lymphoma cells via p21-mediated inhibition of Cdk2 Blood, January 1, 2006; 107(1): 277 - 284. [Abstract] [Full Text] [PDF]
|
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S. J. Kwon, J. J. Song, and Y. J. Lee Signal Pathway of Hypoxia-Inducible Factor-1{alpha} Phosphorylation and its Interaction with von Hippel-Lindau Tumor Suppressor Protein During Ischemia in MiaPaCa-2 Pancreatic Cancer Cells Clin. Cancer Res., November 1, 2005; 11(21): 7607 - 7613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. H. Wenger, D. P. Stiehl, and G. Camenisch Integration of Oxygen Signaling at the Consensus HRE Sci. Signal., October 18, 2005; 2005(306): re12 - re12. [Abstract] [Full Text] [PDF]
|
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|
 |
|
 D. A. Chan, P. D. Sutphin, S.-E. Yen, and A. J. Giaccia Coordinate Regulation of the Oxygen-Dependent Degradation Domains of Hypoxia-Inducible Factor 1{alpha} Mol. Cell. Biol., August 1, 2005; 25(15): 6415 - 6426. [Abstract] [Full Text] [PDF]
|
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|
|
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D. Hargett, T. McLean, and S. L. Bachenheimer Herpes Simplex Virus ICP27 Activation of Stress Kinases JNK and p38 J. Virol., July 1, 2005; 79(13): 8348 - 8360. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K. Jensen, D. J. Manfra, M. G. Grisotto, A. P. Martin, G. Vassileva, K. Kelley, T. W. Schwartz, and S. A. Lira The Human Herpes Virus 8-Encoded Chemokine Receptor Is Required for Angioproliferation in a Murine Model of Kaposi's Sarcoma J. Immunol., March 15, 2005; 174(6): 3686 - 3694. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. A.J. Kempf, M. Lebiedziejewski, K. Alitalo, J.-H. Walzlein, U. Ehehalt, J. Fiebig, S. Huber, B. Schutt, C. A. Sander, S. Muller, et al. Activation of Hypoxia-Inducible Factor-1 in Bacillary Angiomatosis: Evidence for a Role of Hypoxia-Inducible Factor-1 in Bacterial Infections Circulation, March 1, 2005; 111(8): 1054 - 1062. [Abstract] [Full Text] [PDF]
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|
|
|
G. Yuan, J. Nanduri, C. R. Bhasker, G. L. Semenza, and N. R. Prabhakar Ca2+/Calmodulin Kinase-dependent Activation of Hypoxia Inducible Factor 1 Transcriptional Activity in Cells Subjected to Intermittent Hypoxia J. Biol. Chem., February 11, 2005; 280(6): 4321 - 4328. [Abstract] [Full Text] [PDF]
|
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|
|
|
R. Masood, G. Xia, D. L. Smith, P. Scalia, J. G. Still, A. Tulpule, and P. S. Gill Ephrin B2 expression in Kaposi sarcoma is induced by human herpesvirus type 8: phenotype switch from venous to arterial endothelium Blood, February 1, 2005; 105(3): 1310 - 1318. [Abstract] [Full Text] [PDF]
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S. J. Paulsen, M. M. Rosenkilde, J. Eugen-Olsen, and T. N. Kledal Epstein-Barr Virus-Encoded BILF1 Is a Constitutively Active G Protein-Coupled Receptor J. Virol., January 1, 2005; 79(1): 536 - 546. [Abstract] [Full Text] [PDF]
|
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|
|
|
B. Holst, N. D. Holliday, A. Bach, C. E. Elling, H. M. Cox, and T. W. Schwartz Common Structural Basis for Constitutive Activity of the Ghrelin Receptor Family J. Biol. Chem., December 17, 2004; 279(51): 53806 - 53817. [Abstract] [Full Text] [PDF]
|
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|
S. Montaner, A. Sodhi, J.-M. Servitja, A. K. Ramsdell, A. Barac, E. T. Sawai, and J. S. Gutkind The small GTPase Rac1 links the Kaposi sarcoma-associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia Blood, November 1, 2004; 104(9): 2903 - 2911. [Abstract] [Full Text] [PDF]
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K. Hirota, R. Fukuda, S. Takabuchi, S. Kizaka-Kondoh, T. Adachi, K. Fukuda, and G. L. Semenza Induction of Hypoxia-inducible Factor 1 Activity by Muscarinic Acetylcholine Receptor Signaling J. Biol. Chem., October 1, 2004; 279(40): 41521 - 41528. [Abstract] [Full Text] [PDF]
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H.-G. Guo, S. Pati, M. Sadowska, M. Charurat, and M. Reitz Tumorigenesis by Human Herpesvirus 8 vGPCR Is Accelerated by Human Immuodeficiency Virus Type 1 Tat J. Virol., September 1, 2004; 78(17): 9336 - 9342. [Abstract] [Full Text] [PDF]
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M. M. Rosenkilde, K. A. McLean, P. J. Holst, and T. W. Schwartz The CXC Chemokine Receptor Encoded by Herpesvirus saimiri, ECRF3, Shows Ligand-regulated Signaling through Gi, Gq, and G12/13 Proteins but Constitutive Signaling Only through Gi and G12/13 Proteins J. Biol. Chem., July 30, 2004; 279(31): 32524 - 32533. [Abstract] [Full Text] [PDF]
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M. Foster-Cuevas, G. J. Wright, M. J. Puklavec, M. H. Brown, and A. N. Barclay Human Herpesvirus 8 K14 Protein Mimics CD200 in Down-Regulating Macrophage Activation through CD200 Receptor J. Virol., July 15, 2004; 78(14): 7667 - 7676. [Abstract] [Full Text] [PDF]
|
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|
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Y. Liang and D. Ganem RBP-J (CSL) Is Essential for Activation of the K14/vGPCR Promoter of Kaposi's Sarcoma-Associated Herpesvirus by the Lytic Switch Protein RTA J. Virol., July 1, 2004; 78(13): 6818 - 6826. [Abstract] [Full Text] [PDF]
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|
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|
N. Wakisaka, S. Kondo, T. Yoshizaki, S. Murono, M. Furukawa, and J. S. Pagano Epstein-Barr Virus Latent Membrane Protein 1 Induces Synthesis of Hypoxia-Inducible Factor 1{alpha} Mol. Cell. Biol., June 15, 2004; 24(12): 5223 - 5234. [Abstract] [Full Text] [PDF]
|
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|
|
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|
R. Yarchoan KSHV induces heme oxygenase: another trick by a wily virus Blood, May 1, 2004; 103(9): 3252 - 3253. [Full Text] [PDF]
|
|
|
|
|
|
L. Wang, N. Wakisaka, C. C Tomlinson, S. M DeWire, S. Krall, J. S Pagano, and B. Damania The Kaposi's Sarcoma-Associated Herpesvirus (KSHV/HHV-8) K1 Protein Induces Expression of Angiogenic and Invasion Factors Cancer Res., April 15, 2004; 64(8): 2774 - 2781. [Abstract] [Full Text] [PDF]
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 |
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 A. Sodhi, S. Montaner, V. Patel, J. J. Gomez-Roman, Y. Li, E. A. Sausville, E. T. Sawai, and J. S. Gutkind Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor PNAS, April 6, 2004; 101(14): 4821 - 4826. [Abstract] [Full Text] [PDF]
|
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|
|
|
D. Verzijl, C. P. Fitzsimons, M. van Dijk, J. P. Stewart, H. Timmerman, M. J. Smit, and R. Leurs Differential Activation of Murine Herpesvirus 68- and Kaposi's Sarcoma-Associated Herpesvirus-Encoded ORF74 G Protein-Coupled Receptors by Human and Murine Chemokines J. Virol., April 1, 2004; 78(7): 3343 - 3351. [Abstract] [Full Text] [PDF]
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C. Liu, G. Sandford, G. Fei, and J. Nicholas G{alpha} Protein Selectivity Determinant Specified by a Viral Chemokine Receptor-Conserved Region in the C Tail of the Human Herpesvirus 8 G Protein-Coupled Receptor J. Virol., March 1, 2004; 78(5): 2460 - 2471. [Abstract] [Full Text] [PDF]
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|
 |
|
 A. SODHI, S. MONTANER, and J. S. GUTKIND Does dysregulated expression of a deregulated viral GPCR trigger Kaposi's sarcomagenesis? FASEB J, March 1, 2004; 18(3): 422 - 427. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Dadke, B. H. Fryer, E. A. Golemis, and J. Field Activation of p21-Activated Kinase 1-Nuclear Factor {kappa}B Signaling by Kaposi's Sarcoma-Associated Herpes Virus G Protein-Coupled Receptor during Cellular Transformation Cancer Res., December 15, 2003; 63(24): 8837 - 8847. [Abstract] [Full Text] [PDF]
|
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|
|
|
|
Y.-G. Yoo, S. H. Oh, E. S. Park, H. Cho, N. Lee, H. Park, D. K. Kim, D.-Y. Yu, J. K. Seong, and M.-O. Lee Hepatitis B Virus X Protein Enhances Transcriptional Activity of Hypoxia-inducible Factor-1{alpha} through Activation of Mitogen-activated Protein Kinase Pathway J. Biol. Chem., October 3, 2003; 278(40): 39076 - 39084. [Abstract] [Full Text] [PDF]
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|
|
|
S.-k. Park, A. M. Dadak, V. H. Haase, L. Fontana, A. J. Giaccia, and R. S. Johnson Hypoxia-Induced Gene Expression Occurs Solely through the Action of Hypoxia-Inducible Factor 1{alpha} (HIF-1{alpha}): Role of Cytoplasmic Trapping of HIF-2{alpha} Mol. Cell. Biol., July 15, 2003; 23(14): 4959 - 4971. [Abstract] [Full Text] [PDF]
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M. Haque, D. A. Davis, V. Wang, I. Widmer, and R. Yarchoan Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Contains Hypoxia Response Elements: Relevance to Lytic Induction by Hypoxia J. Virol., June 15, 2003; 77(12): 6761 - 6768. [Abstract] [Full Text] [PDF]
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|
 |
|
 L. A. Dourmishev, A. L. Dourmishev, D. Palmeri, R. A. Schwartz, and D. M. Lukac Molecular Genetics of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Epidemiology and Pathogenesis Microbiol. Mol. Biol. Rev., June 1, 2003; 67(2): 175 - 212. [Abstract] [Full Text] [PDF]
|
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|
S. Pati, J. S. Foulke Jr., O. Barabitskaya, J. Kim, B. C. Nair, D. Hone, J. Smart, R. A. Feldman, and M. Reitz Human Herpesvirus 8-Encoded vGPCR Activates Nuclear Factor of Activated T Cells and Collaborates with Human Immunodeficiency Virus Type 1 Tat J. Virol., May 15, 2003; 77(10): 5759 - 5773. [Abstract] [Full Text] [PDF]
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V. Sanz-Moreno, B. Casar, and P. Crespo p38{alpha} Isoform Mxi2 Binds to Extracellular Signal-Regulated Kinase 1 and 2 Mitogen-Activated Protein Kinase and Regulates Its Nuclear Activity by Sustaining Its Phosphorylation Levels Mol. Cell. Biol., May 1, 2003; 23(9): 3079 - 3090. [Abstract] [Full Text] [PDF]
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|
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|
M. C. A. Duyndam, S. T. M. Hulscher, E. van der Wall, H. M. Pinedo, and E. Boven Evidence for a Role of p38 Kinase in Hypoxia-inducible Factor 1-independent Induction of Vascular Endothelial Growth Factor Expression by Sodium Arsenite J. Biol. Chem., February 21, 2003; 278(9): 6885 - 6895. [Abstract] [Full Text] [PDF]
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|
H.-G. Guo, M. Sadowska, W. Reid, E. Tschachler, G. Hayward, and M. Reitz Kaposi's Sarcoma-Like Tumors in a Human Herpesvirus 8 ORF74 Transgenic Mouse J. Virol., February 15, 2003; 77(4): 2631 - 2639. [Abstract] [Full Text] [PDF]
|
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|
|
|
R. D. Estep, M. K. Axthelm, and S. W. Wong A G Protein-Coupled Receptor Encoded by Rhesus Rhadinovirus Is Similar to ORF74 of Kaposi's Sarcoma-Associated Herpesvirus J. Virol., February 1, 2003; 77(3): 1738 - 1746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. Lee, U. H. Koszinowski, S. R. Sarawar, and H. Adler A Gammaherpesvirus G Protein-Coupled Receptor Homologue Is Required for Increased Viral Replication in Response to Chemokines and Efficient Reactivation from Latency J. Immunol., January 1, 2003; 170(1): 243 - 251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Cannon, N. J. Philpott, and E. Cesarman The Kaposi's Sarcoma-Associated Herpesvirus G Protein-Coupled Receptor Has Broad Signaling Effects in Primary Effusion Lymphoma Cells J. Virol., December 6, 2002; 77(1): 57 - 67. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. Coles, P. Diamond, L. Lambrusco, J. Hunter, J. Burrows, M. A. Vadas, and G. J. Goodall A novel mechanism of repression of the vascular endothelial growth factor promoter, by single strand DNA binding cold shock domain (Y-box) proteins in normoxic fibroblasts Nucleic Acids Res., November 15, 2002; 30(22): 4845 - 4854. [Abstract] [Full Text] [PDF]
|
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|
|
|
|
R. Fukuda, K. Hirota, F. Fan, Y. D. Jung, L. M. Ellis, and G. L. Semenza Insulin-like Growth Factor 1 Induces Hypoxia-inducible Factor 1-mediated Vascular Endothelial Growth Factor Expression, Which is Dependent on MAP Kinase and Phosphatidylinositol 3-Kinase Signaling in Colon Cancer Cells J. Biol. Chem., October 4, 2002; 277(41): 38205 - 38211. [Abstract] [Full Text] [PDF]
|
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|
|
|
|
A. G. Polson, D. Wang, J. DeRisi, and D. Ganem Modulation of Host Gene Expression by the Constitutively Active G Protein-coupled Receptor of Kaposi's Sarcoma-associated Herpesvirus Cancer Res., August 1, 2002; 62(15): 4525 - 4530. [Abstract] [Full Text] [PDF]
|
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|
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|
R. H. WENGER Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression FASEB J, August 1, 2002; 16(10): 1151 - 1162. [Abstract] [Full Text] [PDF]
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|
|
F. Spinella, L. Rosano, V. Di Castro, P. G. Natali, and A. Bagnato Endothelin-1 Induces Vascular Endothelial Growth Factor by Increasing Hypoxia-inducible Factor-1alpha in Ovarian Carcinoma Cells J. Biol. Chem., July 26, 2002; 277(31): 27850 - 27855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. V. Moses, M. A. Jarvis, C. Raggo, Y. C. Bell, R. Ruhl, B. G. M. Luukkonen, D. J. Griffith, C. L. Wait, B. J. Druker, M. C. Heinrich, et al. Kaposi's Sarcoma-Associated Herpesvirus-Induced Upregulation of the c-kit Proto-Oncogene, as Identified by Gene Expression Profiling, Is Essential for the Transformation of Endothelial Cells J. Virol., July 17, 2002; 76(16): 8383 - 8399. [Abstract] [Full Text] [PDF]
|
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|
|
|
|
A. Barchowsky, N. V. Soucy, K. A. O'Hara, J. Hwa, T. L. Noreault, and A. S. Andrew A Novel Pathway for Nickel-induced Interleukin-8 Expression J. Biol. Chem., June 28, 2002; 277(27): 24225 - 24231. [Abstract] [Full Text] [PDF]
|
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|
|
|
A. M. Arsham, D. R. Plas, C. B. Thompson, and M. C. Simon Phosphatidylinositol 3-Kinase/Akt Signaling Is Neither Required for Hypoxic Stabilization of HIF-1alpha nor Sufficient for HIF-1-dependent Target Gene Transcription J. Biol. Chem., April 19, 2002; 277(17): 15162 - 15170. [Abstract] [Full Text] [PDF]
|
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|
|
|
|
M. Alvarez-Tejado, A. Alfranca, J. Aragones, A. Vara, M. O. Landazuri, and L. del Peso Lack of Evidence for the Involvement of the Phosphoinositide 3-Kinase/Akt Pathway in the Activation of Hypoxia-inducible Factors by Low Oxygen Tension J. Biol. Chem., April 12, 2002; 277(16): 13508 - 13517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Gao, Y. Li, S. Gee, A. Dudley, J. Fant, C. Crosson, and J.-x. Ma Down-regulation of Vascular Endothelial Growth Factor and Up-regulation of Pigment Epithelium-derived Factor. A POSSIBLE MECHANISM FOR THE ANTI-ANGIOGENIC ACTIVITY OF PLASMINOGEN KRINGLE 5 J. Biol. Chem., March 8, 2002; 277(11): 9492 - 9497. [Abstract] [Full Text] [PDF]
|
|
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|
|
|
L. J. Poole, Y. Yu, P. S. Kim, Q.-Z. Zheng, J. Pevsner, and G. S. Hayward Altered Patterns of Cellular Gene Expression in Dermal Microvascular Endothelial Cells Infected with Kaposi's Sarcoma-Associated Herpesvirus J. Virol., March 7, 2002; 76(7): 3395 - 3420. [Abstract] [Full Text] [PDF]
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M. J. Smit, D. Verzijl, P. Casarosa, M. Navis, H. Timmerman, and R. Leurs Kaposi's Sarcoma-Associated Herpesvirus-Encoded G Protein-Coupled Receptor ORF74 Constitutively Activates p44/p42 MAPK and Akt via Gi and Phospholipase C-Dependent Signaling Pathways J. Virol., February 15, 2002; 76(4): 1744 - 1752. [Abstract] [Full Text] [PDF]
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Y. K. Gruijthuijsen, P. Casarosa, S. J. F. Kaptein, J. L. V. Broers, R. Leurs, C. A. Bruggeman, M. J. Smit, and C. Vink The Rat Cytomegalovirus R33-Encoded G Protein-Coupled Receptor Signals in a Constitutive Fashion J. Virol., February 1, 2002; 76(3): 1328 - 1338. [Abstract] [Full Text] [PDF]
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 R. Masood, E. Cesarman, D. L. Smith, P. S. Gill, and O. Flore Human Herpesvirus-8-Transformed Endothelial Cells Have Functionally Activated Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor Am. J. Pathol., January 1, 2002; 160(1): 23 - 29. [Abstract] [Full Text] [PDF]
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M. C. A. Duyndam, T. M. Hulscher, D. Fontijn, H. M. Pinedo, and E. Boven Induction of Vascular Endothelial Growth Factor Expression and Hypoxia-inducible Factor 1alpha Protein by the Oxidative Stressor Arsenite J. Biol. Chem., December 14, 2001; 276(51): 48066 - 48076. [Abstract] [Full Text] [PDF]
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 R. D. Ye Regulation of nuclear factor {kappa}B activation by G-protein-coupled receptors J. Leukoc. Biol., December 1, 2001; 70(6): 839 - 848. [Abstract] [Full Text] [PDF]
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L. W. Shepard, M. Yang, P. Xie, D. D. Browning, T. Voyno-Yasenetskaya, T. Kozasa, and R. D. Ye Constitutive Activation of NF-kappa B and Secretion of Interleukin-8 Induced by the G Protein-coupled Receptor of Kaposi's Sarcoma-associated Herpesvirus Involve Galpha 13 and RhoA J. Biol. Chem., November 30, 2001; 276(49): 45979 - 45987. [Abstract] [Full Text] [PDF]
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M. Del Corno, Q.-H. Liu, D. Schols, E. de Clercq, S. Gessani, B. D. Freedman, and R. G. Collman HIV-1 gp120 and chemokine activation of Pyk2 and mitogen-activated protein kinases in primary macrophages mediated by calcium-dependent, pertussis toxin-insensitive chemokine receptor signaling Blood, November 15, 2001; 98(10): 2909 - 2916. [Abstract] [Full Text] [PDF]
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 P. C. Mahon, K. Hirota, and G. L. Semenza FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity Genes & Dev., October 15, 2001; 15(20): 2675 - 2686. [Abstract] [Full Text] [PDF]
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S. Pati, M. Cavrois, H.-G. Guo, J. S. Foulke Jr., J. Kim, R. A. Feldman, and M. Reitz Activation of NF-{kappa}B by the Human Herpesvirus 8 Chemokine Receptor ORF74: Evidence for a Paracrine Model of Kaposi's Sarcoma Pathogenesis J. Virol., September 15, 2001; 75(18): 8660 - 8673. [Abstract] [Full Text] [PDF]
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 D. J. WELSH, A. J. PEACOCK, M. MacLEAN, and M. HARNETT Chronic Hypoxia Induces Constitutive p38 Mitogen-activated Protein Kinase Activity That Correlates with Enhanced Cellular Proliferation in Fibroblasts from Rat Pulmonary But Not Systemic Arteries Am. J. Respir. Crit. Care Med., July 15, 2001; 164(2): 282 - 289. [Abstract] [Full Text] [PDF]
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M. Schwarz and P. M. Murphy Kaposi's Sarcoma-Associated Herpesvirus G Protein-Coupled Receptor Constitutively Activates NF-{{kappa}}B and Induces Proinflammatory Cytokine and Chemokine Production Via a C-Terminal Signaling Determinant J. Immunol., July 1, 2001; 167(1): 505 - 513. [Abstract] [Full Text] [PDF]
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S. Montaner, A. Sodhi, S. Pece, E. A. Mesri, and J. S. Gutkind The Kaposi's Sarcoma-associated Herpesvirus G Protein-coupled Receptor Promotes Endothelial Cell Survival through the Activation of Akt/Protein Kinase B Cancer Res., March 1, 2001; 61(6): 2641 - 2648. [Abstract] [Full Text]
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K. Hirota and G. L. Semenza Rac1 Activity Is Required for the Activation of Hypoxia-inducible Factor 1 J. Biol. Chem., June 8, 2001; 276(24): 21166 - 21172. [Abstract] [Full Text] [PDF]
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K. A. Seta, R. Kim, H.-W. Kim, D. E. Millhorn, and D. Beitner-Johnson Hypoxia-induced Regulation of MAPK Phosphatase-1 as Identified by Subtractive Suppression Hybridization and cDNA Microarray Analysis J. Biol. Chem., November 21, 2001; 276(48): 44405 - 44412. [Abstract] [Full Text] [PDF]
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J.-P. Couty, E. Geras-Raaka, B. B. Weksler, and M. C. Gershengorn Kaposi's Sarcoma-associated Herpesvirus G Protein-coupled Receptor Signals through Multiple Pathways in Endothelial Cells J. Biol. Chem., August 31, 2001; 276(36): 33805 - 33811. [Abstract] [Full Text] [PDF]
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