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 (...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2001
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| _version_ | 1826256980673560576 |
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| author | Jaakkola, P Mole, D Tian, Y Wilson, M Gielbert, J Gaskell, S von Kriegsheim, A Hebestreit, H Mukherji, M Schofield, C Maxwell, P Pugh, C Ratcliffe, P |
| author_facet | Jaakkola, P Mole, D Tian, Y Wilson, M Gielbert, J Gaskell, S von Kriegsheim, A Hebestreit, H Mukherji, M Schofield, C Maxwell, P Pugh, C Ratcliffe, P |
| author_sort | Jaakkola, P |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T18:10:53Z |
| format | Journal article |
| id | oxford-uuid:02fba09e-ece5-4c91-a92b-4d91aeec7501 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:10:53Z |
| publishDate | 2001 |
| record_format | dspace |
| spelling | oxford-uuid:02fba09e-ece5-4c91-a92b-4d91aeec75012022-03-26T08:43:41ZTargeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:02fba09e-ece5-4c91-a92b-4d91aeec7501EnglishSymplectic Elements at Oxford2001Jaakkola, PMole, DTian, YWilson, MGielbert, JGaskell, Svon Kriegsheim, AHebestreit, HMukherji, MSchofield, CMaxwell, PPugh, CRatcliffe, PHypoxia-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. |
| spellingShingle | Jaakkola, P Mole, D Tian, Y Wilson, M Gielbert, J Gaskell, S von Kriegsheim, A Hebestreit, H Mukherji, M Schofield, C Maxwell, P Pugh, C Ratcliffe, P Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. |
| title | Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. |
| title_full | Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. |
| title_fullStr | Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. |
| title_full_unstemmed | Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. |
| title_short | Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. |
| title_sort | targeting of hif alpha to the von hippel lindau ubiquitylation complex by o2 regulated prolyl hydroxylation |
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