HIF-1 alpha is required for solid tumor formation and embryonic vascularization

EMBO J. 1998 Jun 1;17(11):3005-15. doi: 10.1093/emboj/17.11.3005.


The transcriptional response to lowered oxygen levels is mediated by the hypoxia-inducible transcription factor (HIF-1), a heterodimer consisting of the constitutively expressed aryl hydrocarbon receptor nuclear translocator (ARNT) and the hypoxic response factor HIF-1alpha. To study the role of the transcriptional hypoxic response in vivo we have targeted the murine HIF-1alpha gene. Loss of HIF-1alpha in embryonic stem (ES) cells dramatically retards solid tumor growth; this is correlated with a reduced capacity to release the angiogenic factor vascular endothelial growth factor (VEGF) during hypoxia. HIF-1alpha null mutant embryos exhibit clear morphological differences by embryonic day (E) 8.0, and by E8.5 there is a complete lack of cephalic vascularization, a reduction in the number of somites, abnormal neural fold formation and a greatly increased degree of hypoxia (measured by the nitroimidazole EF5). These data demonstrate the essential role of HIF-1alpha in controlling both embryonic and tumorigenic responses to variations in microenvironmental oxygenation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Hypoxia / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Embryo, Mammalian / blood supply*
  • Embryo, Mammalian / physiopathology*
  • Gene Deletion
  • Gene Expression Regulation
  • Head / blood supply
  • Head / embryology
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Male
  • Mice
  • Mice, Knockout
  • Nervous System / blood supply
  • Nervous System / embryology
  • Nervous System / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Phosphoglycerate Kinase / biosynthesis
  • Phosphoglycerate Kinase / deficiency
  • Phosphoglycerate Kinase / genetics
  • Stem Cells / metabolism
  • Teratocarcinoma / etiology*
  • Teratocarcinoma / genetics
  • Teratocarcinoma / physiopathology*
  • Transcription Factors*
  • Up-Regulation / genetics
  • Yolk Sac / blood supply


  • DNA-Binding Proteins
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Transcription Factors
  • Phosphoglycerate Kinase