Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.
Science
; 292(5516): 468-72, 2001 Apr 20.
Article
in En
| MEDLINE
| ID: mdl-11292861
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oxygen
/
Transcription Factors
/
Nuclear Proteins
/
Proteins
/
Procollagen-Proline Dioxygenase
/
Tumor Suppressor Proteins
/
Ubiquitin-Protein Ligases
/
DNA-Binding Proteins
/
Hydroxyproline
/
Ligases
Limits:
Humans
Language:
En
Journal:
Science
Year:
2001
Document type:
Article