Regulation of a rat VL30 element in human breast cancer cells in hypoxia and anoxia: role of HIF-1

K Ameri, B Burke, C E Lewis, A L Harris

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Novel approaches to cancer gene therapy currently exploit tumour hypoxia to achieve transcriptional targeting using oxygen-regulated enhancer elements called hypoxia response elements. The activity of such elements in hypoxic cells is directly dependent on upregulation of the hypoxia-inducible transcription factor-1 However tumours also contain areas of anoxia, which may be considered a more tumour-selective transcriptional stimulus than hypoxia for targeting gene therapy to tumours. Another element, from the rat virus-like retrotransposon, VL30 (termed the "secondary anoxia response element") has been reported to be more highly inducible in rat fibroblasts under anoxia than hypoxia. To investigate anoxia as a potential transcriptional target in human tumours, we have examined secondary anoxia response element inducibility in two human breast cancer cell lines, MCF-7 and T47D, under anoxia, hypoxia and normoxia. In both cell types, the trimerised secondary anoxia response element showed greater inducibility in anoxia than hypoxia (1% and 0.5% O(2)). The anoxic response of the secondary anoxia response element was shown to be dependent on hypoxia-inducible transcription factor-1 and the presence of a hypoxia-inducible transcription binding site consensus (5'-ACGTG-3'). Mutational analysis demonstrated that the base immediately 5' to this modulates the anoxic/hypoxic induction of the secondary anoxia response element, such that TACGTG>GACGTG>CACGTG. A similar correlation was found for erythropoietin, phosphoglycerate kinase 1, and aldolase hypoxia response elements, which contain these respective 5' flanking bases.

Original languageEnglish
Pages (from-to)1173-1181
Number of pages9
JournalBritish Journal of Cancer
Volume87
Issue number10
DOIs
Publication statusPublished - 4 Nov 2002

Keywords

  • Animals
  • Breast Neoplasms/genetics
  • CHO Cells
  • Cell Hypoxia
  • Cricetinae
  • DNA-Binding Proteins/analysis
  • Erythropoietin/pharmacology
  • Female
  • Genetic Therapy
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins/analysis
  • Oxygen/pharmacology
  • Rats
  • Response Elements/physiology
  • Retroelements
  • Transcription Factors
  • Tumor Cells, Cultured

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