HIF-1 alpha is required for solid tumor formation and embryonic vascularization.
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.
Ryan
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HE
Department of Biology, University of California, San Diego, La Jolla, CA 92093-0366, USA.
Lo
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J
Johnson
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RS
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian / Q000098:blood supply* / Q000503:physiopathology*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006257:Head / Q000098:blood supply / Q000196:embryology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009420:Nervous System / Q000098:blood supply / Q000196:embryology / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010735:Phosphoglycerate Kinase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism; D018243:Teratocarcinoma / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology*; D014157:Transcription Factors; D015854:Up-Regulation / Q000235:genetics; D015017:Yolk Sac / Q000098:blood supply
D004268:DNA-Binding Proteins; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D010735:Phosphoglycerate Kinase