HIF-1: using two hands to flip the angiogenic switch.
In brain, breast, and other common human tumors there is a correlation between expression of the transcriptional activator hypoxia-inducible factor 1 (HIF-1) and tumor grade and vascularization. HIF-1 stimulates angiogenesis by activating transcription of the gene encoding vascular endothelial growth factor (VEGF). HIF-1 is a heterodimer consisting of a constitutively-expressed HIF-1beta subunit and an O2- and growth factor-regulated HIF-1alpha subunit. Recent studies have demonstrated that HIF-1alpha expression is increased in tumor relative to normal tissue by two mechanisms. First, decreased intratumoral O2 concentrations provide a physiological stimulus. Second, genetic alterations that activate oncogene products or inactivate tumor suppressor gene products increase HIF- 1alpha expression and/or HIF-1 transcriptional activity independent of the O2 concentration. Taken together, these recent data suggest that increased HIF-1 activity provides a molecular basis for VEGF-induced angiogenesis and other adaptations of cancer cells to hypoxia that are critical for establishment of a primary tumor and its progression to the lethal phenotype.
Semenza
G L
GL
Institute of Genetic Medicine, Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. gsemenza@jhmi.edu
D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology*; D016228:Endothelial Growth Factors / Q000235:genetics / Q000502:physiology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines / Q000235:genetics / Q000502:physiology; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology* / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors