The molecular basis of the hypoxia response pathway: tumour hypoxia as a therapy target.
Hypoxia induces a cascade of physiological responses that includes glycolysis, erythropoiesis, angiogenesis, changes in adrenergic signal transduction and vascular cellular proliferation. Hypoxia-inducible genes are relevant to growth and behaviour of cancer as well as the adaptation and survival of normal tissues. Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric DNA binding complex composed of two basic-helix-loop-helix PAS-proteins: HIF-1 beta/ARNT (aryl hydrocarbon receptor nuclear translocator), which is constitutively expressed, and HIF-1 alpha, which is not present in normoxic cells but induced under hypoxic conditions. Recently another member of the bHLH-PAS family, EPAS-1 has been reported and shares similar properties with HIF-1 alpha, although it is considered endothelial specific. In addition, the presence of other DNA-binding motifs in the promoter of hypoxia-inducible genes highlight the occurrence of cross-talk between transcription factors in the modulation of hypoxic gene expression. In this review, we present a survey of the hypoxia response pathway and we discuss attempts to use gene therapy activated by the low oxygen environment or by necrotic regions of tumours.
Imperial Cancer Research Fund, Molecular Oncology Laboratory, University of Oxford, John Radcliffe Hospital, UK.
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D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors