Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.
Hypoxia-inducible factor (HIF) is a transcriptional complex that plays a central role in the regulation of gene expression by oxygen. In oxygenated and iron replete cells, HIF-alpha subunits are rapidly destroyed by a mechanism that involves ubiquitylation by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. This process is ... suppressed by hypoxia and iron chelation, allowing transcriptional activation. Here we show that the interaction between human pVHL and a specific domain of the HIF-1alpha subunit is regulated through hydroxylation of a proline residue (HIF-1alpha P564) by an enzyme we have termed HIF-alpha prolyl-hydroxylase (HIF-PH). An absolute requirement for dioxygen as a cosubstrate and iron as cofactor suggests that HIF-PH functions directly as a cellular oxygen sensor.
Mesh Terms:
Amino Acid Sequence, Ascorbic Acid, Cell Hypoxia, DNA-Binding Proteins, Deferoxamine, Ferrous Compounds, Humans, Hydroxylation, Hydroxyproline, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Ligases, Molecular Sequence Data, Nuclear Proteins, Oxygen, Point Mutation, Procollagen-Proline Dioxygenase, Protein Structure, Tertiary, Proteins, Recombinant Fusion Proteins, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Transcription Factors, Tumor Cells, Cultured, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Ubiquitins, Von Hippel-Lindau Tumor Suppressor Protein
Amino Acid Sequence, Ascorbic Acid, Cell Hypoxia, DNA-Binding Proteins, Deferoxamine, Ferrous Compounds, Humans, Hydroxylation, Hydroxyproline, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Ligases, Molecular Sequence Data, Nuclear Proteins, Oxygen, Point Mutation, Procollagen-Proline Dioxygenase, Protein Structure, Tertiary, Proteins, Recombinant Fusion Proteins, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Transcription Factors, Tumor Cells, Cultured, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Ubiquitins, Von Hippel-Lindau Tumor Suppressor Protein
Science
Date: Apr. 20, 2001
PubMed ID: 11292861
View in: Pubmed Google Scholar
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