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https://hdl.handle.net/2440/27998
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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 1083-351X |
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 Humans Cysteine DNA-(Apurinic or Apyrimidinic Site) Lyase Carbon-Oxygen Lyases Serine DNA-Binding Proteins Nuclear Proteins Recombinant Proteins Transcription Factors Oligonucleotides, Antisense DNA Mutagenesis, Site-Directed Gene Expression Regulation Amino Acid Sequence Helix-Loop-Helix Motifs Sequence Homology, Amino Acid Oxidation-Reduction Molecular Sequence Data Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit |
DOI: | 10.1074/jbc.275.7.4618 |
Published version: | http://www.jbc.org/cgi/content/abstract/275/7/4618 |
Appears in Collections: | Aurora harvest 6 Centre for the Molecular Genetics of Development publications Molecular and Biomedical Science publications |
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