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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mazure, N. M. Articles by Giaccia, A. J. Search for Related Content PubMed PubMed Citation Articles by Mazure, N. M. Articles by Giaccia, A. J. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RAPID COMMUNICATION Induction of Vascular Endothelial Growth Factor by Hypoxia Is Modulated by a Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in Ha-ras-Transformed Cells Through a Hypoxia Inducible Factor-1 Transcriptional Element Nathalie M. Mazure, Eunice Y. Chen, Keith R. Laderoute, and Amato J. Giaccia From the Mayer Cancer Biology Research Laboratory, the Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA; and SRI International Pharmaceutical Discovery Division, Menlo Park, CA. Tumor angiogenesis, the development of new blood vessels, is a highly regulated process that is controlled genetically by alterations in oncogene and tumor suppressor gene expression and physiologically by the tumor microenvironment. Previous studies indicate that the angiogenic switch in Ras-transformed cells may be physiologically promoted by the tumor microenvironment through the induction of the angiogenic mitogen, vascular endothelial growth factor (VEGF). In this report, we show Ras-transformed cells do not use the downstream effectors c-Raf-1 or mitogen activated protein kinases (MAPK) in signaling VEGF induction by hypoxia as overexpression of kinase-defective alleles of these genes does not inhibit VEGF induction under low oxygen conditions. In contrast to the c-Raf-1/MAP kinase pathway, hypoxia increases phosphatidylinositol 3-kinase (PI 3-kinase) activity in a Ras-dependent manner, and inhibition of PI 3-kinase activity genetically and pharmacologically results in inhibition of VEGF induction. We propose that hypoxia modulates VEGF induction in Ras-transformed cells through the activation of a stress inducible PI 3-kinase/Akt pathway and the hypoxia inducible factor-1 (HIF-1) transcriptional response element. Blood, Vol. 90 No. 9 (November 1), 1997: pp. 3322-3331 © 1997 by The American Society of Hematology. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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Jaffe Lysophosphatidic Acid Induction of Vascular Endothelial Growth Factor Expression in Human Ovarian Cancer Cells J Natl Cancer Inst, May 16, 2001; 93(10): 762 - 767. [Abstract] [Full Text] [PDF] A. Jones, C. Fujiyama, C. Blanche, J. W. Moore, S. Fuggle, D. Cranston, R. Bicknell, and Adrian. L. Harris Relation of Vascular Endothelial Growth Factor Production to Expression and Regulation of Hypoxia-inducible Factor-1{{alpha}} and Hypoxia-inducible Factor-2{{alpha}} in Human Bladder Tumors and Cell Lines Clin. Cancer Res., May 1, 2001; 7(5): 1263 - 1272. [Abstract] [Full Text] I. Kosmidou, A. Xagorari, C. Roussos, and A. Papapetropoulos Reactive oxygen species stimulate VEGF production from C2C12 skeletal myotubes through a PI3K/Akt pathway Am J Physiol Lung Cell Mol Physiol, April 1, 2001; 280(4): L585 - L592. [Abstract] [Full Text] [PDF] E. Y. Chen, N. M. Mazure, J. A. Cooper, and A. J. Giaccia Hypoxia Activates a Platelet-derived Growth Factor Receptor/Phosphatidylinositol 3-Kinase/Akt Pathway That Results in Glycogen Synthase Kinase-3 Inactivation Cancer Res., March 1, 2001; 61(6): 2429 - 2433. [Abstract] [Full Text] R. Bos, H. Zhong, C. F. Hanrahan, E. C. M. Mommers, G. L. Semenza, H. M. Pinedo, M. D. Abeloff, J. W. Simons, P. J. van Diest, and E. van der Wall Levels of Hypoxia-Inducible Factor-1{{alpha}} During Breast Carcinogenesis J Natl Cancer Inst, February 21, 2001; 93(4): 309 - 314. [Abstract] [Full Text] [PDF] H. Chen, A. T. Treweeke, D. C. West, K. J. Till, J. C. Cawley, M. Zuzel, and C. H. Toh In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells Blood, November 1, 2000; 96(9): 3181 - 3187. [Abstract] [Full Text] [PDF] S. Dimmeler and A. M. Zeiher Endothelial Cell Apoptosis in Angiogenesis and Vessel Regression Circ. Res., September 15, 2000; 87(6): 434 - 439. [Abstract] [Full Text] [PDF] A. Sodhi, S. Montaner, V. Patel, M. Zohar, C. Bais, E. A. Mesri, and J. S. Gutkind The Kaposi's Sarcoma-associated Herpes Virus G Protein-coupled Receptor Up-Regulates Vascular Endothelial Growth Factor Expression and Secretion through Mitogen-activated Protein Kinase and p38 Pathways Acting on Hypoxia-inducible Factor 1{{alpha}} Cancer Res., September 1, 2000; 60(17): 4873 - 4880. [Abstract] [Full Text] G. L. Semenza HIF-1 and human disease: one highly involved factor Genes & Dev., August 15, 2000; 14(16): 1983 - 1991. [Full Text] L. M. Ellis and G. E. Gallick Promiscuous Transcription of Vascular Endothelial Growth Factor and Survival of Tumors J Natl Cancer Inst, July 5, 2000; 92(13): 1030 - 1031. [Full Text] [PDF] K. Inoue, J. W. Slaton, D. W. Davis, D. J. Hicklin, D. J. McConkey, T. Karashima, R. Radinsky, and C. P. N. Dinney Treatment of Human Metastatic Transitional Cell Carcinoma of the Bladder in a Murine Model with the Anti-Vascular Endothelial Growth Factor Receptor Monoclonal Antibody DC101 and Paclitaxel Clin. Cancer Res., July 1, 2000; 6(7): 2635 - 2643. [Abstract] [Full Text] K. R. Laderoute, R. M. Alarcon, M. D. Brody, J. M. Calaoagan, E. Y. Chen, A. M. Knapp, Z. Yun, N. C. Denko, and A. J. Giaccia Opposing Effects of Hypoxia on Expression of the Angiogenic Inhibitor Thrombospondin 1 and the Angiogenic Inducer Vascular Endothelial Growth Factor Clin. Cancer Res., July 1, 2000; 6(7): 2941 - 2950. [Abstract] [Full Text] J. M. Fredriksson, J. M. Lindquist, G. E. Bronnikov, and J. Nedergaard Norepinephrine Induces Vascular Endothelial Growth Factor Gene Expression in Brown Adipocytes through a beta -Adrenoreceptor/cAMP/Protein Kinase A Pathway Involving Src but Independently of Erk1/2 J. Biol. Chem., April 28, 2000; 275(18): 13802 - 13811. [Abstract] [Full Text] [PDF] W. Zundel, L. M. Swiersz, and A. Giaccia Caveolin 1-Mediated Regulation of Receptor Tyrosine Kinase-Associated Phosphatidylinositol 3-Kinase Activity by Ceramide Mol. Cell. Biol., March 1, 2000; 20(5): 1507 - 1514. [Abstract] [Full Text] H. Zhong, K. Chiles, D. Feldser, E. Laughner, C. Hanrahan, M.-M. Georgescu, J. W. Simons, and G. L. Semenza Modulation of Hypoxia-inducible Factor 1{{alpha}} 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., March 1, 2000; 60(6): 1541 - 1545. [Abstract] [Full Text]

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