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PMID:8756616

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Citation

Forsythe, JA, Jiang, BH, Iyer, NV, Agani, F, Leung, SW, Koos, RD and Semenza, GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell. Biol. 16:4604-13

Abstract

Expression of vascular endothelial growth factor (VEGF) is induced in cells exposed to hypoxia or ischemia. Neovascularization stimulated by VEGF occurs in several important clinical contexts, including myocardial ischemia, retinal disease, and tumor growth. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix protein that activates transcription of the human erythropoietin gene in hypoxic cells. Here we demonstrate the involvement of HIF-1 in the activation of VEGF transcription. VEGF 5'-flanking sequences mediated transcriptional activation of reporter gene expression in hypoxic Hep3B cells. A 47-bp sequence located 985 to 939 bp 5' to the VEGF transcription initiation site mediated hypoxia-inducible reporter gene expression directed by a simian virus 40 promoter element that was otherwise minimally responsive to hypoxia. When reporters containing VEGF sequences, in the context of the native VEGF or heterologous simian virus 40 promoter, were cotransfected with expression vectors encoding HIF-1alpha and HIF-1beta (ARNT [aryl hydrocarbon receptor nuclear translocator]), reporter gene transcription was much greater in both hypoxic and nonhypoxic cells than in cells transfected with the reporter alone. A HIF-1 binding site was demonstrated in the 47-bp hypoxia response element, and a 3-bp substitution eliminated the ability of the element to bind HIF-1 and to activate transcription in response to hypoxia and/or recombinant HIF-1. Cotransfection of cells with an expression vector encoding a dominant negative form of HIF-1alpha inhibited the activation of reporter transcription in hypoxic cells in a dose-dependent manner. VEGF mRNA was not induced by hypoxia in mutant cells that do not express the HIF-1beta (ARNT) subunit. These findings implicate HIF-1 in the activation of VEGF transcription in hypoxic cells.

Links

PubMed PMC231459

Keywords

Animals; Base Sequence; Carcinoma, Hepatocellular/pathology; Cell Hypoxia; DNA-Binding Proteins/chemistry; DNA-Binding Proteins/physiology; Endothelial Growth Factors/biosynthesis; Endothelial Growth Factors/genetics; Gene Expression Regulation; Genes, Reporter; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms/pathology; Lymphokines/biosynthesis; Lymphokines/genetics; Mice; Molecular Sequence Data; Nuclear Proteins/chemistry; Nuclear Proteins/physiology; Promoter Regions, Genetic; Rats; Recombinant Fusion Proteins/metabolism; Sequence Alignment; Sequence Homology, Nucleic Acid; Simian virus 40/genetics; Transcription Factors; Transcription, Genetic; Transfection; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ARNT

part_of

GO:0090575: RNA polymerase II transcription regulator complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ARNT

involved_in

GO:0001938: positive regulation of endothelial cell proliferation

ECO:0000305: curator inference used in manual assertion

GO:0010575

P

Seeded From UniProt

complete

HUMAN:ARNT

involved_in

GO:0001666: response to hypoxia

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ARNT

involved_in

GO:0030949: positive regulation of vascular endothelial growth factor receptor signaling pathway

ECO:0000305: curator inference used in manual assertion

GO:0010575

P

Seeded From UniProt

complete

HUMAN:ARNT

involved_in

GO:0010575: positive regulation of vascular endothelial growth factor production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ARNT

contributes_to

GO:0000981: DNA-binding transcription factor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0000165)

Seeded From UniProt

complete

HUMAN:HIF1A

part_of

GO:0090575: RNA polymerase II transcription regulator complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:HIF1A

contributes_to

GO:0000981: DNA-binding transcription factor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0000165)

Seeded From UniProt

complete

HUMAN:HIF1A

involved_in

GO:0001666: response to hypoxia

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HIF1A

involved_in

GO:0045766: positive regulation of angiogenesis

ECO:0000305: curator inference used in manual assertion

GO:0010575

P

Seeded From UniProt

complete

HUMAN:HIF1A

part_of

GO:0090575: RNA polymerase II transcription factor complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:HIF1A

contributes_to

GO:0043565: sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:HIF1A

involved_in

GO:0030949: positive regulation of vascular endothelial growth factor receptor signaling pathway

ECO:0000305: curator inference used in manual assertion

GO:0010575

P

Seeded From UniProt

complete

HUMAN:HIF1A

involved_in

GO:0010575: positive regulation of vascular endothelial growth factor production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HIF1A

contributes_to

GO:0000981: DNA-binding transcription factor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

occurs_at:(SO:0000165)

Seeded From UniProt

complete

HUMAN:HIF1A

involved_in

GO:0001938: positive regulation of endothelial cell proliferation

ECO:0000305: curator inference used in manual assertion

GO:0010575

P

Seeded From UniProt

complete


See also

References

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