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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 Wiesener, M.S. Articles by Maxwell, P.H. Search for Related Content PubMed PubMed Citation Articles by Wiesener, M.S. Articles by Maxwell, P.H. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, Vol. 92 No. 7 (October 1), 1998: pp. 2260-2268 Induction of Endothelial PAS Domain Protein-1 by Hypoxia: Characterization and Comparison With Hypoxia-Inducible Factor-1 M.S. Wiesener, H. Turley, W.E. Allen, C. Willam, K.-U. Eckardt, K.L. Talks, S.M. Wood, K.C. Gatter, A.L. Harris, C.W. Pugh, P.J. Ratcliffe, and P.H. Maxwell From the Institute of Molecular Medicine and the Department of Cellular Science, John Radcliffe Hospital, Oxford, UK; and Klinikum der Charité, Humboldt Universtät, Berlin, Germany. Hypoxia results in adaptive changes in the transcription of a range of genes including erythropoietin. An important mediator is hypoxia-inducible factor-1 (HIF-1), a DNA binding complex shown to contain at least two basic helix-loop-helix PAS-domain (bHLH-PAS) proteins, HIF-1 and aryl hydrocarbon nuclear receptor translocator (ARNT). In response to hypoxia, HIF-1 is activated and accumulates rapidly in the cell. Endothelial PAS domain protein 1 (EPAS-1) is a recently identified bHLH-PAS protein with 48% identity to HIF-1, raising the question of its role in responses to hypoxia. We developed specific antibodies and studied expression and regulation of EPAS-1 mRNA and protein across a range of human cell lines. EPAS-1 was widely expressed, and strongly induced by hypoxia at the level of protein but not mRNA. Comparison of the effect of a range of activating and inhibitory stimuli showed striking similarities in the EPAS-1 and HIF-1 responses. Although major differences were observed in the abundance of EPAS-1 and HIF-1 in different cell types, differences in the inducible response were subtle with EPAS-1 protein being slightly more evident in normoxic and mildly hypoxic cells. Functional studies in a mutant cell line (Ka13) expressing neither HIF-1 nor EPAS-1 confirmed that both proteins interact with hypoxically responsive targets, but suggest target specificity with greater EPAS-1 transactivation (relative to HIF-1 transactivation) of the VEGF promoter than the LDH-A promoter. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K.G. Pringle, K.L. Kind, A.N. Sferruzzi-Perri, J.G. Thompson, and C.T. 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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] T. S. Gross, N. Akeno, T. L. Clemens, S. Komarova, S. Srinivasan, D. A. Weimer, and S. Mayorov Physiological and Genomic Consequences of Intermittent Hypoxia: Selected Contribution: Osteocytes upregulate HIF-1{alpha} in response to acute disuse and oxygen deprivation J Appl Physiol, June 1, 2001; 90(6): 2514 - 2519. [Abstract] [Full Text] [PDF] A. Krones, K. Jungermann, and T. Kietzmann Cross-Talk between the Signals Hypoxia and Glucose at the Glucose Response Element of the L-Type Pyruvate Kinase Gene Endocrinology, June 1, 2001; 142(6): 2707 - 2718. [Abstract] [Full Text] [PDF] S. C. Clifford, M. E. Cockman, A. C. Smallwood, D. R. Mole, E. R. Woodward, P. H. Maxwell, P. J. Ratcliffe, and E. R. Maher Contrasting effects on HIF-1{{alpha}} regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease Hum. Mol. Genet., May 1, 2001; 10(10): 1029 - 1038. [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] M. I. Koukourakis, A. Giatromanolaki, J. Skarlatos, L. Corti, S. Blandamura, M. Piazza, K. C. Gatter, and A. L. Harris Hypoxia Inducible Factor (HIF-1a and HIF-2a) Expression in Early Esophageal Cancer and Response to Photodynamic Therapy and Radiotherapy Cancer Res., March 1, 2001; 61(5): 1830 - 1832. [Abstract] [Full Text] C. C. Wykoff, N. Beasley, P. H. Watson, L. Campo, S. K. Chia, R. English, J. Pastorek, W. S. Sly, P. Ratcliffe, and A. L. Harris Expression of the Hypoxia-Inducible and Tumor-Associated Carbonic Anhydrases in Ductal Carcinoma in Situ of the Breast Am. J. Pathol., March 1, 2001; 158(3): 1011 - 1019. [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] B. Jiang, A. Kamat, and C. R. Mendelson Hypoxia Prevents Induction of Aromatase Expression in Human Trophoblast Cells in Culture: Potential Inhibitory Role of the Hypoxia-Inducible Transcription Factor Mash-2 (Mammalian Achaete-Scute Homologous Protein-2) Mol. Endocrinol., October 1, 2000; 14(10): 1661 - 1673. [Abstract] [Full Text] C. Willam, P. Koehne, J. S. Jurgensen, M. Grafe, K. D. Wagner, S. Bachmann, U. Frei, and K.-U. Eckardt Tie2 Receptor Expression Is Stimulated by Hypoxia and Proinflammatory Cytokines in Human Endothelial Cells Circ. Res., September 1, 2000; 87(5): 370 - 377. [Abstract] [Full Text] [PDF] R. M. Wanner, P. Spielmann, D. M. Stroka, G. Camenisch, I. Camenisch, A. Scheid, D. R. Houck, C. Bauer, M. Gassmann, and R. H. Wenger Epolones induce erythropoietin expression via hypoxia-inducible factor-1alpha activation Blood, August 15, 2000; 96(4): 1558 - 1565. [Abstract] [Full Text] [PDF] X. Ren, K. L. Dorrington, P. H. Maxwell, and P. A. Robbins Effects of desferrioxamine on serum erythropoietin and ventilatory sensitivity to hypoxia in humans J Appl Physiol, August 1, 2000; 89(2): 680 - 686. [Abstract] [Full Text] [PDF] T. Kietzmann, J. Fandrey, and H. Acker Oxygen Radicals as Messengers in Oxygen-Dependent Gene Expression Physiology, August 1, 2000; 15(4): 202 - 208. [Abstract] [Full Text] [PDF] 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] J. Peng, L. Zhang, L. Drysdale, and G.-H. Fong The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling PNAS, June 30, 2000; (2000) 140087397. [Abstract] [Full Text] S. J. Mandriota, C. Pyke, C. Di Sanza, P. Quinodoz, B. Pittet, and M. S. Pepper Hypoxia-Inducible Angiopoietin-2 Expression Is Mimicked by Iodonium Compounds and Occurs in the Rat Brain and Skin in Response to Systemic Hypoxia and Tissue Ischemia Am. J. Pathol., June 1, 2000; 156(6): 2077 - 2089. [Abstract] [Full Text] [PDF] C. Clerici and M. A. Matthay Hypoxia regulates gene expression of alveolar epithelial transport proteins J Appl Physiol, May 1, 2000; 88(5): 1890 - 1896. [Abstract] [Full Text] [PDF] G. L. Semenza HIF-1: mediator of physiological and pathophysiological responses to hypoxia J Appl Physiol, April 1, 2000; 88(4): 1474 - 1480. [Abstract] [Full Text] [PDF] A. L. Harris von Hippel-Lindau Syndrome: Target for Anti-Vascular Endothelial Growth Factor (VEGF) Receptor Therapy Oncologist, April 1, 2000; 5(90001): 32 - 36. [Abstract] [Full Text] H. J. H. Marti, M. Bernaudin, A. Bellail, H. Schoch, M. Euler, E. Petit, and W. Risau Hypoxia-Induced Vascular Endothelial Growth Factor Expression Precedes Neovascularization after Cerebral Ischemia Am. J. Pathol., March 1, 2000; 156(3): 965 - 976. [Abstract] [Full Text] [PDF] D. Lando, I. Pongratz, L. Poellinger, and M. L. Whitelaw A Redox Mechanism Controls Differential DNA Binding Activities of Hypoxia-inducible Factor (HIF) 1alpha and the HIF-like Factor J. Biol. Chem., February 18, 2000; 275(7): 4618 - 4627. [Abstract] [Full Text] [PDF] R. Wenger Mammalian oxygen sensing, signalling and gene regulation J. Exp. Biol., January 4, 2000; 203(8): 1253 - 1263. [Abstract] [PDF] A. Ouiddir, C. Planès, I. Fernandes, A. VanHesse, and C. Clerici Hypoxia Upregulates Activity and Expression of the Glucose Transporter GLUT1 in Alveolar Epithelial Cells Am. J. Respir. Cell Mol. Biol., December 1, 1999; 21(6): 710 - 718. [Abstract] [Full Text] P. W. Conrad, T. L. Freeman, D. Beitner-Johnson, and D. E. Millhorn EPAS1 trans-Activation during Hypoxia Requires p42/p44 MAPK J. Biol. Chem., November 19, 1999; 274(47): 33709 - 33713. [Abstract] [Full Text] [PDF] K. Maemura, C.-M. Hsieh, M. K. Jain, S. Fukumoto, M. D. Layne, Y. Liu, S. Kourembanas, S.-F. Yet, M. A. Perrella, and M.-E. Lee Generation of a Dominant-negative Mutant of Endothelial PAS Domain Protein 1 by Deletion of a Potent C-terminal Transactivation Domain J. Biol. Chem., October 29, 1999; 274(44): 31565 - 31570. [Abstract] [Full Text] [PDF] D. M. Adelman, E. Maltepe, and M. C. Simon Multilineage embryonic hematopoiesis requires hypoxic ARNT activity Genes & Dev., October 1, 1999; 13(19): 2478 - 2483. [Abstract] [Full Text] B. L. Ebert and H. F. Bunn Regulation of the Erythropoietin Gene Blood, September 15, 1999; 94(6): 1864 - 1877. [Full Text] [PDF] E. Metzen, J. Fandrey, and W. Jelkmann Evidence against a major role for Ca2+ in hypoxia-induced gene expression in human hepatoma cells (Hep3B) J. Physiol., June 15, 1999; 517(3): 651 - 657. [Abstract] [Full Text] [PDF]

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