PMID- 11795592
OWN - NLM
STAT- MEDLINE
DCOM- 20020725
LR  - 20220410
IS  - 1521-6543 (Print)
IS  - 1521-6543 (Linking)
VI  - 52
IP  - 1-2
DP  - 2001 Jul
TI  - Regulation of HIF by the von Hippel-Lindau tumour suppressor: implications for 
      cellular oxygen sensing.
PG  - 43-7
AB  - Hypoxia-inducible factor (HIF) is central in coordinating many of the 
      transcriptional adaptations to hypoxia. Composed of a heterodimer of alpha and 
      beta subunits, the alpha subunit is rapidly degraded in normoxia, leading to 
      inactivation of the hypoxic response. Many models for a molecular oxygen sensor 
      regulating this system have been proposed, but an important finding has been the 
      ability to mimic hypoxia by chelation or substitution of iron. A key insight has 
      been the recognition that HIF-alpha is targeted for degradation by the 
      ubiquitin-proteasome pathway through binding to the von Hippel-Lindau tumour 
      suppressor protein (pVHL), which forms the recognition component of an E3 
      ubiquitin ligase complex leading to ubiquitylation of HIF-alpha. Importantly, the 
      classical features of regulation by iron and oxygen availability are reflected in 
      regulation of the HIF-alpha/pVHL interaction. It has recently been shown that 
      HIF-alpha undergoes an iron- and oxygen-dependent modification before it can 
      interact with pVHL, and that this results in hydroxylation of at least one prolyl 
      residue (HIF-1alpha, Pro 564). This modification is catalysed by an enzyme termed 
      HIF-prolyl hydroxylase (HIF-PH), and compatible with all previously described 
      prolyl-4-hydroxylases HIF-PH also requires 2-oxoglutarate as a cosubstrate. The 
      key position of this hydroxylation in the degradation pathway of HIF-alpha, 
      together with its requirement for molecular dioxygen as a co-substrate, provides 
      the potential for HIF-PH to function directly as a cellular oxygen sensor. 
      However, the ability of these enzyme(s) to account for the full range of 
      physiological regulation displayed by the HIF system remains to be defined.
FAU - Mole, D R
AU  - Mole DR
AD  - The Henry Wellcome Building of Genomic Medicine, University of Oxford, United 
      Kingdom.
FAU - Maxwell, P H
AU  - Maxwell PH
FAU - Pugh, C W
AU  - Pugh CW
FAU - Ratcliffe, P J
AU  - Ratcliffe PJ
LA  - eng
PT  - Journal Article
PT  - Review
PL  - England
TA  - IUBMB Life
JT  - IUBMB life
JID - 100888706
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - EC 6.- (Ligases)
RN  - EC 6.3.2.- (VHL protein, human)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Animals
MH  - Basic Helix-Loop-Helix Transcription Factors
MH  - Cysteine Endopeptidases/metabolism
MH  - DNA-Binding Proteins/*metabolism
MH  - Humans
MH  - Hydroxylation
MH  - Hypoxia/metabolism
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Ligases/*metabolism
MH  - Multienzyme Complexes/metabolism
MH  - Nuclear Proteins/*metabolism
MH  - Oxygen/*metabolism
MH  - Proteasome Endopeptidase Complex
MH  - Protein Binding
MH  - Trans-Activators/*metabolism
MH  - *Transcription Factors
MH  - *Tumor Suppressor Proteins
MH  - *Ubiquitin-Protein Ligases
MH  - Von Hippel-Lindau Tumor Suppressor Protein
RF  - 38
EDAT- 2002/01/25 10:00
MHDA- 2002/07/26 10:01
CRDT- 2002/01/25 10:00
PHST- 2002/01/25 10:00 [pubmed]
PHST- 2002/07/26 10:01 [medline]
PHST- 2002/01/25 10:00 [entrez]
AID - 10.1080/15216540252774757 [doi]
PST - ppublish
SO  - IUBMB Life. 2001 Jul;52(1-2):43-7. doi: 10.1080/15216540252774757.