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J Biol Chem, Vol. 274, Issue 4, 2060-2071, January 22, 1999
From the Erythropoietin Group, Room 425, Institute of Molecular
Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, United Kingdom
Endothelial PAS protein 1 (EPAS1) is a basic
helix-loop-helix Per-AHR-ARNT-Sim transcription factor related to
hypoxia-inducible factor-1
(HIF-1). To analyze EPAS1 domains
responsible for transactivation and oxygen-regulated function, we
constructed chimeric fusions of EPAS1 with a GAL4 DNA binding domain,
plus or minus the VP16 activation domain. Two transactivation domains
were defined in EPAS1; a C-terminal domain (amino acids 828-870), and
a larger internal domain (amino acids 517-682). These activation
domains were interspersed by functionally repressive sequences, several of which independently conveyed oxygen-regulated activity. Two types of
activity were defined. Sequences lying N-terminal to and overlapping
the internal transactivation domain conferred regulated repression on
the VP16 transactivator. Sequences lying C-terminal to this internal
domain conveyed repression and oxygen-regulated activity on the native
EPAS1 C-terminal activation domain, but not the Gal/VP16 fusion.
Fusions containing internal but not C-terminal regulatory domains
manifested regulation of fusion protein level. Comparison of EPAS1 with
HIF-1 demonstrated a similar organization for both proteins, and for
the C terminus defined a conserved RLL motif critical for inducibility.
Overall, EPAS1 sequences were less inducible than those of HIF-1,
and inducibility was strikingly reduced as their expression level was
increased. Despite these quantitative differences, EPAS1 regulation
appeared similar to HIF-1, conforming to a model involving the
modulation of both protein level and activity, through distinct
internal and C-terminal domains.
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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]
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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]
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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]
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M. E. Cockman, N. Masson, D. R. Mole, P. Jaakkola, G.-W. Chang, S. C. Clifford, E. R. Maher, C. W. Pugh, P. J. Ratcliffe, and P. H. Maxwell Hypoxia Inducible Factor-alpha Binding and Ubiquitylation by the von Hippel-Lindau Tumor Suppressor Protein J. Biol. Chem., August 11, 2000; 275(33): 25733 - 25741. [Abstract] [Full Text] [PDF]
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J. Gu, J. Milligan, and L. E. Huang Molecular Mechanism of Hypoxia-inducible Factor 1alpha -p300 Interaction. A LEUCINE-RICH INTERFACE REGULATED BY A SINGLE CYSTEINE J. Biol. Chem., January 26, 2001; 276(5): 3550 - 3554. [Abstract] [Full Text] [PDF]
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C. H. Sutter, E. Laughner, and G. L. Semenza Hypoxia-inducible factor 1alpha protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations PNAS, April 25, 2000; 97(9): 4748 - 4753. [Abstract] [Full Text] [PDF]
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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, July 18, 2000; 97(15): 8386 - 8391. [Abstract] [Full Text] [PDF]
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