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

Journal article

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.

Authors: Jaakkola, P; Mole, D; Tian, Y; Wilson, M; Gielbert, J

• Publication status: Published
• Journal: Science (New York, N.Y.)
• Volume: 292
• Issue: 5516
• Pages: 468-472
• Publication date: 2001-04-01
• DOI: 10.1126/science.1059796
• EISSN: 1095-9203
• ISSN: 0036-8075
• Language: English
• Keywords: Hydroxyproline; Recombinant Fusion Proteins; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Proteins; Procollagen-Proline Dioxygenase; Ferrous Compounds; Tumor Suppressor Proteins; Deferoxamine; DNA-Binding Proteins; Transcription Factors; Ubiquitins; Ubiquitin-Protein Ligases; Protein Structure, Tertiary; Nuclear Proteins; Hydroxylation; Ligases; Ascorbic Acid; Humans; Von Hippel-Lindau Tumor Suppressor Protein; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor 1; Cell Hypoxia; Tumor Cells, Cultured; Oxygen; Point Mutation; Molecular Sequence Data; Amino Acid Sequence