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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.]
The elucidation of the molecular mechanisms governing the transition
from a nonangiogenic to an angiogenic phenotype is central for
understanding and controlling malignancies. Viral oncogenes represent
powerful tools for disclosing transforming mechanisms, and they may
also afford the possibility of investigating the relationship between
transforming pathways and angiogenesis. In this regard, we have
recently observed that a constitutively active G protein-coupled
receptor (GPCR) encoded by the Kaposis sarcoma-associated herpes
virus (KSHV)/human herpes virus 8 is oncogenic and stimulates
angiogenesis by increasing the secretion of vascular endothelial growth
factor (VEGF), which is a key angiogenic stimulator and a critical
mitogen for the development of Kaposis sarcoma. Here we show that the
KSHV GPCR enhances the expression of VEGF by stimulating the activity
of the transcription factor hypoxia-inducible factor (HIF)-1
, 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 Kaposis sarcoma
and other neoplastic diseases.
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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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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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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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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] |
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