PMID- 9510527
OWN - NLM
STAT- MEDLINE
DCOM- 19980818
LR  - 20220216
IS  - 0022-0949 (Print)
IS  - 0022-0949 (Linking)
VI  - 201
IP  - Pt 8
DP  - 1998 Apr
TI  - Oxygen sensing, hypoxia-inducible factor-1 and the regulation of mammalian gene 
      expression.
PG  - 1153-62
AB  - A great many aspects of the anatomy and physiology of large animals are 
      constrained by the need to match oxygen supply to cellular metabolism and appear 
      likely to involve the regulation of gene expression by oxygen. Some insight into 
      possible underlying mechanisms has been provided by studies of erythropoietin, a 
      haemopoietic growth factor which stimulates red cell production in response to 
      hypoxia. Studies of hypoxia-inducible cis-acting sequences from the 
      erythropoietin gene have led to the recognition of a widespread transcriptional 
      response to hypoxia based on the activation of a DNA-binding complex termed 
      hypoxia-inducible factor-1 (HIF-1). Perturbation of the transcriptional response 
      by particular transition metal ions, iron chelators and certain redox-active 
      agents have suggested a specific oxygen sensing mechanism, perhaps involving a 
      haem protein in a flavoprotein/cytochrome system. In addition to erythropoietin, 
      HIF-1-responsive genes include examples with functions in cellular energy 
      metabolism, iron metabolism, catecholamine metabolism, vasomotor control and 
      angiogenesis, suggesting an important role in the coordination of oxygen supply 
      and cellular metabolism. In support of this, we have demonstrated an important 
      role for HIF-1 in tumour angiogenesis. HIF-1 itself consists of a heterodimer of 
      two basic-helix-loop-helix proteins of the PAS family, termed HIF-1alpha and 
      HIF-1beta, although other closely related members of this family may also 
      contribute to the response to hypoxia. We have fused domains of HIF-1 genes to 
      heterologous transcription factors to assay for regulatory function. These 
      experiments have defined several domains in HIF-1alpha which can independently 
      confer the hypoxia-inducible property, and they suggest a mechanism of HIF-1 
      activation in which post-translational activation/derepression of HIF-1alpha is 
      amplified by changes in HIF-1alpha abundance most probably arising from 
      suppression of proteolytic breakdown. Pursuit of the mechanism(s) underlying 
      these processes should ultimately lead to better definition of the oxygen-sensing 
      process.
FAU - Ratcliffe, P J
AU  - Ratcliffe PJ
AD  - Erythropoietin Group, Institute of Molecular Medicine, John Radcliffe Hospital, 
      Headington, Oxford OX3 9DS, UK. peter.ratcliffe@hammer.imm.ox.ac.uk
FAU - O'Rourke, J F
AU  - O'Rourke JF
FAU - Maxwell, P H
AU  - Maxwell PH
FAU - Pugh, C W
AU  - Pugh CW
LA  - eng
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - England
TA  - J Exp Biol
JT  - The Journal of experimental biology
JID - 0243705
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 (Nuclear Proteins)
RN  - 0 (Transcription Factors)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Animals
MH  - Cell Hypoxia/genetics/physiology
MH  - DNA-Binding Proteins/*genetics/*physiology
MH  - Evolution, Molecular
MH  - Gene Expression Regulation/*physiology
MH  - Humans
MH  - Hypoxia/*genetics/*metabolism
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Nuclear Proteins/*genetics/*physiology
MH  - Oxygen/*metabolism/*physiology
MH  - *Transcription Factors
RF  - 67
EDAT- 1998/05/29 00:00
MHDA- 1998/05/29 00:01
CRDT- 1998/05/29 00:00
PHST- 1998/05/29 00:00 [pubmed]
PHST- 1998/05/29 00:01 [medline]
PHST- 1998/05/29 00:00 [entrez]
AID - 10.1242/jeb.201.8.1153 [doi]
PST - ppublish
SO  - J Exp Biol. 1998 Apr;201(Pt 8):1153-62. doi: 10.1242/jeb.201.8.1153.