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PMID: 11641274 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity.

Genes & development ·Vol. 15 ·No. 20 ·2001-10-15 ·Pages 2675-86

Mahon PC, Hirota K, Semenza GL

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a master regulator of oxygen homeostasis that controls angiogenesis, erythropoiesis, and glycolysis via transcriptional activation of target genes under hypoxic conditions. O(2)-dependent binding of the von Hippel-Lindau (VHL) tumor suppressor protein targets the HIF-1alpha subunit for ubiquitination and proteasomal degradation. The activity of the HIF-1alpha transactivation domains is also O(2) regulated by a previously undefined mechanism. Here, we report the identification of factor inhibiting HIF-1 (FIH-1), a protein that binds to HIF-1alpha and inhibits its transactivation function. In addition, we demonstrate that FIH-1 binds to VHL and that VHL also functions as a transcriptional corepressor that inhibits HIF-1alpha transactivation function by recruiting histone deacetylases. Involvement of VHL in association with FIH-1 provides a unifying mechanism for the modulation of HIF-1alpha protein stabilization and transcriptional activation in response to changes in cellular O(2) concentration.

MeSH Terms
Amino Acid Sequence Animals Cell Hypoxia/physiology Cells, Cultured DNA Primers/chemistry DNA-Binding Proteins Fungal Proteins/metabolism Gene Expression Regulation Glutathione Transferase/metabolism Histone Deacetylases/metabolism Humans Hypoxia-Inducible Factor 1, alpha Subunit In Vitro Techniques Ligases/metabolism Luciferases/metabolism Mixed Function Oxygenases Molecular Sequence Data Nuclear Proteins/genetics,metabolism Oxygen/metabolism Polymerase Chain Reaction Protein Conformation Rabbits Repressor Proteins/genetics,metabolism Reticulocytes/metabolism Saccharomyces cerevisiae Saccharomyces cerevisiae Proteins Sequence Homology, Amino Acid Signal Transduction/physiology Transcription Factors/genetics,metabolism Transcription, Genetic Transcriptional Activation Tumor Suppressor Proteins Two-Hybrid System Techniques Ubiquitin-Protein Ligases Von Hippel-Lindau Tumor Suppressor Protein
Chemicals
DNA Primers DNA-Binding Proteins Fungal Proteins GAL4 protein, S cerevisiae HIF1A protein, human Hypoxia-Inducible Factor 1, alpha Subunit Nuclear Proteins Repressor Proteins Saccharomyces cerevisiae Proteins Transcription Factors Tumor Suppressor Proteins Mixed Function Oxygenases Luciferases HIF1AN protein, human Ubiquitin-Protein Ligases Von Hippel-Lindau Tumor Suppressor Protein Glutathione Transferase Histone Deacetylases Ligases VHL protein, human Oxygen
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Mahon P C
Institute of Genetic Medicine, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914, USA.
Hirota K
Semenza G L
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.924501
Published
2001-10-15
Pages
2675-86
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC312814
Subset
IM
Grants
NIDDK NIH HHS · R01-DK39869 · United States
Databases
GENBANK
AF395830
External Links
PubMed source DOI: 10.1101/gad.924501 PMC Full Text View journal details
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