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V-SRC Induces Expression of Hypoxia-inducible Factor 1 (HIF-1) and Transcription of Genes Encoding Vascular Endothelial Growth Factor and Enolase 1: Involvement of HIF-1 in Tumor Progression¹

Center for Medical Genetics, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914 [B-H. J., F. A., G. L. S.], and National Institute on Aging, NIH, Baltimore, Maryland 21224 [A. P.]

Adaptation to hypoxia represents an important aspect of tumor progression. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates essential homeostatic responses to cellular and systemic hypoxia by activating transcription of multiple genes including those encoding glycolytic enzymes and vascular endothelial growth factor (VEGF). In this report, we demonstrate that whereas C-SRC expression is not required for expression of HIF-1 or transcriptional activation of genes encoding VEGF and enolase 1 (ENO1), cells expressing the v-Src oncogene have increased expression of HIF-1, VEGF, and ENO1 under both hypoxic and nonhypoxic conditions. Expression of V-SRC was associated with increased transcription of reporter genes containing cis-acting hypoxia-response elements from the VEGF and ENO1 genes, and this transcriptional activation required an intact HIF-1 binding site. When three rat hepatoma subclones that differed with respect to the level of HIF-1 expression were injected into nude mice, tumor growth correlated with HIF-1 expression, suggesting that HIF-1 may be generally involved in tumor progression. These studies link an oncogene to the induction of HIF-1 expression, thus providing a mechanism for hypoxic adaptation by tumor cells.

¹ This work was supported by grants from the American Heart Association National Center and National Institutes of Health (R01-HL55338 and R01-DK39869). G. L. S. is an Established Investigator of the American Heart Association.

² To whom requests for reprints should be addressed, at Center for Medical Genetics, Johns Hopkins Hospital, CMSC-1004, 600 North Wolfe Street, Baltimore, MD 21287-3914. Phone: (410) 955-1619; Fax: (410) 955-0484; E-mail: gsemenza@gwgate1.jhmi.jhu.edu.

Received 6/13/97. Accepted 10/ 3/97.

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				L. Xu, D. Fukumura, and R. K. Jain Acidic Extracellular pH Induces Vascular Endothelial Growth Factor (VEGF) in Human Glioblastoma Cells via ERK1/2 MAPK Signaling Pathway. MECHANISM OF LOW pH-INDUCED VEGF J. Biol. Chem., March 22, 2002; 277(13): 11368 - 11374. [Abstract] [Full Text] [PDF]

				J. R. Griffiths, P. M. J. McSheehy, S. P. Robinson, H. Troy, Y.-L. Chung, R. D. Leek, K. J. Williams, I. J. Stratford, A. L. Harris, and M. Stubbs Metabolic Changes Detected by in Vivo Magnetic Resonance Studies of HEPA-1 Wild-Type Tumors and Tumors Deficient in Hypoxia-inducible Factor-1{beta} (HIF-1{beta}): Evidence of an Anabolic Role for the HIF-1 Pathway Cancer Res., February 1, 2002; 62(3): 688 - 695. [Abstract] [Full Text] [PDF]

				A. Alfranca, M. D. Gutierrez, A. Vara, J. Aragones, F. Vidal, and M. O. Landazuri c-Jun and Hypoxia-Inducible Factor 1 Functionally Cooperate in Hypoxia-Induced Gene Transcription Mol. Cell. Biol., January 1, 2002; 22(1): 12 - 22. [Abstract] [Full Text] [PDF]

				D. M. STROKA, T. BURKHARDT, I. DESBAILLETS, R. H. WENGER, D. A. H. NEIL, C. BAUER, M. GASSMANN, and D. CANDINAS HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia FASEB J, November 1, 2001; 15(13): 2445 - 2453. [Abstract] [Full Text] [PDF]

				C. Blancher, J. W. Moore, N. Robertson, and A. L. Harris Effects of ras and von Hippel-Lindau (VHL) Gene Mutations on Hypoxia-inducible Factor (HIF)-1{alpha}, HIF-2{alpha}, and Vascular Endothelial Growth Factor Expression and Their Regulation by the Phosphatidylinositol 3'-Kinase/Akt Signaling Pathway Cancer Res., October 1, 2001; 61(19): 7349 - 7355. [Abstract] [Full Text] [PDF]

				V. Vukovic, H. K. Haugland, T. Nicklee, A. J. Morrison, and D. W. Hedley Hypoxia-inducible Factor-1{alpha} Is an Intrinsic Marker for Hypoxia in Cervical Cancer Xenografts Cancer Res., October 1, 2001; 61(20): 7394 - 7398. [Abstract] [Full Text] [PDF]

				A. Orimo, Y. Tomioka, Y. Shimizu, M. Sato, S. Oigawa, K. Kamata, Y. Nogi, S. Inoue, M. Takahashi, T. Hata, et al. Cancer-associated Myofibroblasts Possess Various Factors to Promote Endometrial Tumor Progression Clin. Cancer Res., October 1, 2001; 7(10): 3097 - 3105. [Abstract] [Full Text] [PDF]

				B.-H. Jiang, G. Jiang, J. Z. Zheng, Z. Lu, T. Hunter, and P. K. Vogt Phosphatidylinositol 3-Kinase Signaling Controls Levels of Hypoxia-inducible Factor 1 Cell Growth Differ., July 1, 2001; 12(7): 363 - 369. [Abstract] [Full Text] [PDF]

				M. S. Wiesener, P. M. Munchenhagen, I. Berger, N. V. Morgan, J. Roigas, A. Schwiertz, J. S. Jurgensen, G. Gruber, P. H. Maxwell, S. A. Loning, et al. Constitutive Activation of Hypoxia-inducible Genes Related to Overexpression of Hypoxia-inducible Factor-1{{alpha}} in Clear Cell Renal Carcinomas Cancer Res., July 1, 2001; 61(13): 5215 - 5222. [Abstract] [Full Text] [PDF]

				E. Laughner, P. Taghavi, K. Chiles, P. C. Mahon, and G. L. Semenza HER2 (neu) Signaling Increases the Rate of Hypoxia-Inducible Factor 1{alpha} (HIF-1{alpha}) Synthesis: Novel Mechanism for HIF-1-Mediated Vascular Endothelial Growth Factor Expression Mol. Cell. Biol., June 15, 2001; 21(12): 3995 - 4004. [Abstract] [Full Text]

				Q. Shi, X. Le, J. L. Abbruzzese, Z. Peng, C.-N. Qian, H. Tang, Q. Xiong, B. Wang, X.-C. Li, and K. Xie Constitutive Sp1 Activity Is Essential for Differential Constitutive Expression of Vascular Endothelial Growth Factor in Human Pancreatic Adenocarcinoma Cancer Res., May 1, 2001; 61(10): 4143 - 4154. [Abstract] [Full Text]

				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]

				E. Hur, K. Y. Chang, E. Lee, S.-K. Lee, and H. Park Mitogen-Activated Protein Kinase Kinase Inhibitor PD98059 Blocks the trans-Activation but Not the Stabilization or DNA Binding Ability of Hypoxia-Inducible Factor-1alpha Mol. Pharmacol., April 16, 2001; 59(5): 1216 - 1224. [Abstract] [Full Text]

				D. M. Aebersold, P. Burri, K. T. Beer, J. Laissue, V. Djonov, R. H. Greiner, and G. L. Semenza Expression of Hypoxia-inducible Factor-1{{alpha}}: A Novel Predictive and Prognostic Parameter in the Radiotherapy of Oropharyngeal Cancer Cancer Res., April 1, 2001; 61(7): 2911 - 2916. [Abstract] [Full Text]

				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]

				A. Rajakumar, K. A. Whitelock, L. A. Weissfeld, A. R. Daftary, N. Markovic, and K. P. Conrad Selective Overexpression of the Hypoxia-Inducible Transcription Factor, HIF-2{{alpha}}, in Placentas from Women with Preeclampsia Biol Reprod, February 1, 2001; 64(2): 499 - 506. [Abstract] [Full Text]

				C. C. Wykoff, N. J. P. Beasley, P. H. Watson, K. J. Turner, J. Pastorek, A. Sibtain, G. D. Wilson, H. Turley, K. L. Talks, P. H. Maxwell, et al. Hypoxia-inducible Expression of Tumor-associated Carbonic Anhydrases Cancer Res., December 1, 2000; 60(24): 7075 - 7083. [Abstract] [Full Text]

				C. Blancher, J. W. Moore, K. L. Talks, S. Houlbrook, and A. L. Harris Relationship of Hypoxia-inducible Factor (HIF)-1{{alpha}} and HIF-2{{alpha}} Expression to Vascular Endothelial Growth Factor Induction and Hypoxia Survival in Human Breast Cancer Cell Lines Cancer Res., December 1, 2000; 60(24): 7106 - 7113. [Abstract] [Full Text]

				D. A. Elson, H. E. Ryan, J. W. Snow, R. Johnson, and J. M. Arbeit Coordinate Up-Regulation of Hypoxia Inducible Factor (HIF)-1{{alpha}} and HIF-1 Target Genes during Multi-Stage Epidermal Carcinogenesis and Wound Healing Cancer Res., November 1, 2000; 60(21): 6189 - 6195. [Abstract] [Full Text]

				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]

				K. L. Talks, H. Turley, K. C. Gatter, P. H. Maxwell, C. W. Pugh, P. J. Ratcliffe, and A. L. Harris The Expression and Distribution of the Hypoxia-Inducible Factors HIF-1{alpha} and HIF-2{alpha} in Normal Human Tissues, Cancers, and Tumor-Associated Macrophages Am. J. Pathol., August 1, 2000; 157(2): 411 - 421. [Abstract] [Full Text] [PDF]

				A. Rajakumar and K. P. Conrad Expression, Ontogeny, and Regulation of Hypoxia-Inducible Transcription Factors in the Human Placenta Biol Reprod, August 1, 2000; 63(2): 559 - 569. [Abstract] [Full Text]

				L. Zhang, D. Yu, M. Hu, S. Xiong, A. Lang, L. M. Ellis, and R. E. Pollock Wild-Type p53 Suppresses Angiogenesis in Human Leiomyosarcoma and Synovial Sarcoma by Transcriptional Suppression of Vascular Endothelial Growth Factor Expression Cancer Res., July 1, 2000; 60(13): 3655 - 3661. [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]