Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O 2 -Regulated Prolyl Hydroxylation
10.1126/science.1059796
Crossref journal-article
American Association for the Advancement of Science (AAAS)
Science (221)
Abstract

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-α 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-1α subunit is regulated through hydroxylation of a proline residue (HIF-1α P564) by an enzyme we have termed HIF-α 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.

Bibliography

Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. von, Hebestreit, H. F., Mukherji, M., Schofield, C. J., Maxwell, P. H., Pugh, ‡ Christopher W., & Ratcliffe, ‡ Peter J. (2001). Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O 2 -Regulated Prolyl Hydroxylation. Science, 292(5516), 468–472.

Authors 13
  1. Panu Jaakkola (first)
  2. David R. Mole (additional)
  3. Ya-Min Tian (additional)
  4. Michael I. Wilson (additional)
  5. Janine Gielbert (additional)
  6. Simon J. Gaskell (additional)
  7. Alexander von Kriegsheim (additional)
  8. Holger F. Hebestreit (additional)
  9. Mridul Mukherji (additional)
  10. Christopher J. Schofield (additional)
  11. Patrick H. Maxwell (additional)
  12. ‡ Christopher W. Pugh (additional)
  13. ‡ Peter J. Ratcliffe (additional)
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Dates
Type When
Created 17 years, 9 months ago (Nov. 12, 2007, 11:27 a.m.)
Deposited 1 year, 7 months ago (Jan. 9, 2024, 5:04 p.m.)
Indexed 18 hours, 32 minutes ago (Aug. 26, 2025, 2:53 a.m.)
Issued 24 years, 4 months ago (April 20, 2001)
Published 24 years, 4 months ago (April 20, 2001)
Published Print 24 years, 4 months ago (April 20, 2001)
Funders 0

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@article{Jaakkola_2001, title={Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O 2 -Regulated Prolyl Hydroxylation}, volume={292}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1059796}, DOI={10.1126/science.1059796}, number={5516}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Jaakkola, Panu and Mole, David R. and Tian, Ya-Min and Wilson, Michael I. and Gielbert, Janine and Gaskell, Simon J. and Kriegsheim, Alexander von and Hebestreit, Holger F. and Mukherji, Mridul and Schofield, Christopher J. and Maxwell, Patrick H. and Pugh, ‡ Christopher W. and Ratcliffe, ‡ Peter J.}, year={2001}, month=apr, pages={468–472} }