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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 Kaposi’s 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 Kaposi’s 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 Kaposi’s sarcoma
and other neoplastic diseases.
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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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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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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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R. Yarchoan KSHV induces heme oxygenase: another trick by a wily virus Blood, May 1, 2004; 103(9): 3252 - 3253. [Full Text] [PDF]
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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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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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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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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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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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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]
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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]
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 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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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]
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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]
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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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