Ameri, K., Burke, B., Lewis, C. E. et al. (1 more author) (2002) Regulation of a rat VL30 element in human breast cancer cells in hypoxia and anoxia: role of HIF-1. British Journal of Cancer, 87 (10). pp. 1173-1181. ISSN 0007-0920
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% O2). 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2002 Cancer Research UK. BJC Open. https://creativecommons.org/licenses/by-nc-sa/3.0/ |
Keywords: | anoxia; hypoxia; VL30; retrotransposon; HRE; gene therapy; PAS DOMAIN PROTEIN-1; INDUCIBLE FACTOR-1; GENE-EXPRESSION; TRANSCRIPTION FACTOR; RECOGNITION SITE; BINDING; INDUCTION; RETROTRANSPOSON; HIF-1-ALPHA; ENHANCER |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 21 Nov 2016 11:26 |
Last Modified: | 21 Nov 2016 11:27 |
Published Version: | http://dx.doi.org/10.1038/sj.bjc.6600576 |
Status: | Published |
Publisher: | Cancer Research UK |
Refereed: | Yes |
Identification Number: | 10.1038/sj.bjc.6600576 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:107886 |
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Licence: CC-BY-NC-SA 3.0