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Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.

Science (New York, N.Y.) | Apr 20, 2001

http://www.ncbi.nlm.nih.gov/pubmed/11292861

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.

Pubmed ID: 11292861 RIS Download

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

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