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Type: Journal article
Title: A redox mechanism controls differential DNA binding activities of hypoxia-inducible factor (HIF) 1a and the HIF-like factor
Author: Lando, D.
Pongratz, I.
Poellinger, L.
Whitelaw, M.
Citation: Journal of Biological Chemistry, 2000; 275(7):4618-4627
Publisher: Amer Soc Biochemistry Molecular Biology Inc
Issue Date: 2000
ISSN: 0021-9258
Organisation: Centre for the Molecular Genetics of Development
Abstract: Hypoxia-inducible factor 1α (HIF-1α) and the HIF-like factor (HLF) are two highly related basic Helix-Loop-Helix/Per-Arnt-Sim (bHLH/PAS) homology transcription factors that undergo dramatically increased function at low oxygen levels. Despite strong similarities in their activation mechanisms (e.g. they both undergo rapid hypoxia-induced protein stabilization, bind identical target DNA sequences, and induce synthetic reporter genes to similar degrees), they are both essential for embryo survival via distinct functions during vascularization (HIF-1α) or catecholamine production (HLF). It is currently unknown how such specificity of action is achieved. We report here that DNA binding by HLF, but not by HIF-1α, is dependent upon reducing redox conditions. In vitro DNA binding and mammalian two-hybrid assays showed that a unique cysteine in the DNA-binding basic region of HLF is a target for the reducing activity of redox factor Ref-1. Although the N-terminal DNA-binding domain of HIF-1α can function in the absence of Ref-1, we found that the C-terminal region containing the transactivation domain requires Ref-1 for full activity. Our data reveal that the hypoxia-inducible factors are subject to complex redox control mechanisms that can target discrete regions of the proteins and are the first to establish a discriminating control mechanism for differential regulation of HIF-1α and HLF activity.
Keywords: Hela Cells
DNA-(Apurinic or Apyrimidinic Site) Lyase
Carbon-Oxygen Lyases
DNA-Binding Proteins
Nuclear Proteins
Recombinant Proteins
Transcription Factors
Oligonucleotides, Antisense
Mutagenesis, Site-Directed
Gene Expression Regulation
Amino Acid Sequence
Helix-Loop-Helix Motifs
Sequence Homology, Amino Acid
Molecular Sequence Data
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit
DOI: 10.1074/jbc.275.7.4618
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Appears in Collections:Aurora harvest 6
Centre for the Molecular Genetics of Development publications
Molecular and Biomedical Science publications

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