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.
Blancher
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Imperial Cancer Research Fund, Molecular Oncology Laboratory, University of Oxford, John Radcliffe Hospital, UK.
Harris
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AL
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