Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 292 (5516), 468-72

Targeting of HIF-alpha to the Von Hippel-Lindau Ubiquitylation Complex by O2-regulated Prolyl Hydroxylation

Affiliations

Targeting of HIF-alpha to the Von Hippel-Lindau Ubiquitylation Complex by O2-regulated Prolyl Hydroxylation

P Jaakkola et al. Science.

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-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.

Comment in

  • Signal Transduction. How Do Cells Sense Oxygen?
    H Zhu et al. Science 292 (5516), 449-51. PMID 11292863.
    How do organisms sense the amount of oxygen in the environment and respond appropriately when the amount of oxygen decreases (a condition called hypoxia)? In their Perspe …

Similar articles

See all similar articles

Cited by 1,531 PubMed Central articles

See all "Cited by" articles

Publication types

MeSH terms

Substances

LinkOut - more resources

Feedback