Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
50
pubmed:dateCreated
1997-1-17
pubmed:abstractText
Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor that is critical for hypoxic induction of a number of physiologically important genes. We present evidence that regulation of HIF-1 activity is primarily determined by the stability of the HIF-1alpha protein. Both HIF-1alpha and HIF-1beta mRNAs were constitutively expressed in HeLa and Hep3B cells with no significant induction by hypoxia. However, the HIF-1alpha protein was barely detectable in normoxic cells, even when HIF-1alpha was overexpressed, but was highly induced in hypoxic cells, whereas HIF-1beta protein levels remained constant, regardless of pO2. Hypoxia-induced HIF-1 binding as well as the HIF-1alpha protein were rapidly and drastically decreased in vivo following an abrupt increase to normal oxygen tension. Moreover, short pre-exposure of cells to hydrogen peroxide selectively prevented hypoxia-induced HIF-1 binding via blocking accumulation of HIF-1alpha protein, whereas treatment of hypoxic cell extracts with H2O2 had no effect on HIF-1 binding. These observations suggest that an intact redox-dependent signaling pathway is required for destablization of the HIF-1alpha protein. In hypoxic cell extracts, HIF-1 DNA binding was reversibly abolished by sulfhydryl oxidation. Furthermore, the addition of reduced thioredoxin to cell extracts enhanced HIF-1 DNA binding. Consistent with these results, overexpression of thioredoxin and Ref-1 significantly potentiated hypoxia-induced expression of a reporter construct containing the wild-type HIF-1 binding site. These experiments indicate that activation of HIF-1 involves redox-dependent stabilization of HIF-1alpha protein.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
13
pubmed:volume
271
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
32253-9
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:8943284-Blotting, Western, pubmed-meshheading:8943284-DNA, pubmed-meshheading:8943284-DNA-Binding Proteins, pubmed-meshheading:8943284-Electrophoresis, Polyacrylamide Gel, pubmed-meshheading:8943284-Erythropoietin, pubmed-meshheading:8943284-Gene Expression Regulation, pubmed-meshheading:8943284-HeLa Cells, pubmed-meshheading:8943284-Helix-Loop-Helix Motifs, pubmed-meshheading:8943284-Humans, pubmed-meshheading:8943284-Hydrogen Peroxide, pubmed-meshheading:8943284-Hypoxia-Inducible Factor 1, pubmed-meshheading:8943284-Hypoxia-Inducible Factor 1, alpha Subunit, pubmed-meshheading:8943284-Nuclear Proteins, pubmed-meshheading:8943284-Oxidation-Reduction, pubmed-meshheading:8943284-Protein Conformation, pubmed-meshheading:8943284-Sulfhydryl Reagents, pubmed-meshheading:8943284-Transcription Factors
pubmed:year
1996
pubmed:articleTitle
Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit.
pubmed:affiliation
Hematology-Oncology Division, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. Bunn@calvin.bwh.harvard.edu
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't