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Publication type: Journal Article
Document type: Full Paper

Year: 2003

Author(s): Park, SK; Dadak, AM; Haase, VH; Fontana, L; Giaccia, AJ; Johnson, RS

Title: Hypoxia-induced gene expression occurs solely through the action of hypoxia-inducible factor 1alpha (HIF-1alpha): role of cytoplasmic trapping of HIF-2alpha.

Source: Mol Cell Biol (23), 14 4959-4971.



Authors Vetmeduni Vienna:

Dadak Agnes


Project(s): Activation and function of hypoxia inducible transcription factors


Abstract:
The hypoxia-inducible factors 1alpha (HIF-1alpha) and 2alpha (HIF-2alpha) have extensive structural homology and have been identified as key transcription factors responsible for gene expression in response to hypoxia. They play critical roles not only in normal development, but also in tumor progression. Here we report on the differential regulation of protein expression and transcriptional activity of HIF-1alpha and -2alpha by hypoxia in immortalized mouse embryo fibroblasts (MEFs). We show that oxygen-dependent protein degradation is restricted to HIF-1alpha, as HIF-2alpha protein is detected in MEFs regardless of oxygenation and is localized primarily to the cytoplasm. Endogenous HIF-2alpha remained transcriptionally inactive under hypoxic conditions; however, ectopically overexpressed HIF-2alpha translocated into the nucleus and could stimulate expression of hypoxia-inducible genes. We show that the factor inhibiting HIF-1 can selectively inhibit the transcriptional activity of HIF-1alpha but has no effect on HIF-2alpha-mediated transcription in MEFs. We propose that HIF-2alpha is not a redundant transcription factor of HIF-1alpha for hypoxia-induced gene expression and show evidence that there is a cell type-specific modulator(s) that enables selective activation of HIF-1alpha but not HIF-2alpha in response to low-oxygen stress.

Keywords Pubmed: Animals
Basic Helix-Loop-Helix Transcription Factors
Cell Compartmentation
Cell Hypoxia/physiology*
Cell Nucleus/genetics
Cell Nucleus/metabolism
Cells, Cultured
Cytoplasm/metabolism*
Embryo, Mammalian/cytology
Endothelial Growth Factors/genetics
Fibroblasts/cytology
Fibroblasts/metabolism
Gene Expression Regulation/physiology*
Glucose Transporter Type 1
Hypoglycemia/genetics
Hypoglycemia/metabolism
Hypoxia-Inducible Factor 1, alpha Subunit
Intercellular Signaling Peptides and Proteins/genetics
Ligases/genetics
Ligases/metabolism
Lymphokines/genetics
Mice
Mice, Mutant Strains
Mixed Function Oxygenases
Monosaccharide Transport Proteins/genetics
Oxygen/metabolism
Peptide Hydrolases/metabolism
Phosphoglycerate Kinase/genetics
Phosphoglycerate Kinase/metabolism
Proteasome Endopeptidase Complex*
Repressor Proteins/genetics
Repressor Proteins/metabolism
Signal Transduction
Trans-Activators/genetics
Trans-Activators/metabolism*
Transcription Factors/genetics
Transcription Factors/metabolism*
Transcription, Genetic
Tumor Suppressor Proteins*
Ubiquitin-Protein Ligases*
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
Von Hippel-Lindau Tumor Suppressor Protein


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