A redox mechanism controls differential DNA binding activities of hypoxia-inducible factor (HIF) 1a and the HIF-like factor

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dc.contributor.authorLando, D.
dc.contributor.authorPongratz, I.
dc.contributor.authorPoellinger, L.
dc.contributor.authorWhitelaw, M.
dc.contributor.organisationCentre for the Molecular Genetics of Development
dc.date.issued2000
dc.description.abstractHypoxia-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.
dc.identifier.citationJournal of Biological Chemistry, 2000; 275(7):4618-4627
dc.identifier.doi10.1074/jbc.275.7.4618
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.urihttp://hdl.handle.net/2440/27998
dc.language.isoen
dc.publisherAmer Soc Biochemistry Molecular Biology Inc
dc.source.urihttp://www.jbc.org/cgi/content/abstract/275/7/4618
dc.subjectHela Cells
dc.subjectHumans
dc.subjectCysteine
dc.subjectDNA-(Apurinic or Apyrimidinic Site) Lyase
dc.subjectCarbon-Oxygen Lyases
dc.subjectSerine
dc.subjectDNA-Binding Proteins
dc.subjectNuclear Proteins
dc.subjectRecombinant Proteins
dc.subjectTranscription Factors
dc.subjectOligonucleotides, Antisense
dc.subjectDNA
dc.subjectMutagenesis, Site-Directed
dc.subjectGene Expression Regulation
dc.subjectAmino Acid Sequence
dc.subjectHelix-Loop-Helix Motifs
dc.subjectSequence Homology, Amino Acid
dc.subjectOxidation-Reduction
dc.subjectMolecular Sequence Data
dc.subjectHypoxia-Inducible Factor 1
dc.subjectHypoxia-Inducible Factor 1, alpha Subunit
dc.titleA redox mechanism controls differential DNA binding activities of hypoxia-inducible factor (HIF) 1a and the HIF-like factor
dc.typeJournal article
pubs.publication-statusPublished

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