Activity of hypoxia-inducible factor 2alpha is regulated by association with the NF-kappaB essential modulator.
The hypoxia-inducible factors 1alpha (HIF-1alpha) and 2alpha (HIF-2alpha) are key regulators of the transcriptional response to low oxygen and are closely related in domain architecture, DNA binding, and activation mechanisms. Despite these similarities, targeted disruption of the HIF-alpha genes in mice results in distinctly different phenotypes demonstrating nonredundancy of function, ... although the underlying mechanisms remain unclear. Here we report on the novel and specific interaction of HIF-2alpha, but not HIF-1alpha, with the NF-kappaB essential modulator (NEMO) using immunoprecipitation, mammalian two-hybrid, and in vitro protein interaction assays. Reporter gene assays demonstrate that this interaction specifically enhances normoxic HIF-2alpha transcriptional activity, independently of the HIF-2alpha transactivation domain, consistent with a model by which NEMO aids CBP/p300 recruitment to HIF-2alpha. In contrast, HIF-2alpha overexpression does not alter NF-kappaB signaling, suggesting that the functional consequence of the HIF-2alpha/NEMO interaction is limited to the HIF pathway. The specificity of NEMO for HIF-2alpha represents one of the few known differential protein-protein interactions between the HIF-alpha proteins, which has important implications for the activity of HIF-2alpha and is also the first postulated NF-kappaB-independent role for NEMO.
Mesh Terms:
Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Line, E1A-Associated p300 Protein, Gene Expression Regulation, Genes, Reporter, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, I-kappa B Kinase, Mice, Nuclear Proteins, Oligonucleotides, Antisense, Protein-Serine-Threonine Kinases, Recombinant Fusion Proteins, Signal Transduction, Trans-Activators, Transcription Factors, Transcription, Genetic, Two-Hybrid System Techniques
Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Line, E1A-Associated p300 Protein, Gene Expression Regulation, Genes, Reporter, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, I-kappa B Kinase, Mice, Nuclear Proteins, Oligonucleotides, Antisense, Protein-Serine-Threonine Kinases, Recombinant Fusion Proteins, Signal Transduction, Trans-Activators, Transcription Factors, Transcription, Genetic, Two-Hybrid System Techniques
J. Biol. Chem.
Date: Apr. 08, 2005
PubMed ID: 15653678
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