Enhancement of gene expression under hypoxic conditions using fragments of the human vascular endothelial growth factor and the erythropoietin genes

Shibata, Toru; Akiyama, Nobutake; Noda, Makoto; Sasai, Keisuke; Hiraoka, Masahiro

doi:10.1016/s0360-3016(98)00298-3

Cited by 87 publications

(65 citation statements)

References 17 publications

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“…All constructs were verified by sequencing. The expression plasmids pCEP4-HIF-1a and pcDNA3-HIF-2a and the 5xHRE/hCMVmp-luc reporter construct were previously described (Forsythe et al, 1996;Tian et al, 1997;Shibata et al, 1998). Full-length HIF-2a-Flag was constructed by digestion of pcDNA3-HIF-2a using BamHI and cloning into the p3XFLAG-CMVt-10 expression vector (Sigma, St Louis, MO, USA).…”

Section: Cloning Plasmids and Rnaimentioning

confidence: 99%

The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2α

et al. 2007

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Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that play a crucial role in oxygen homeostasis. Intratumoral hypoxia and genetic alterations lead to HIF activity, which is a hallmark of solid cancer and is associated with poor clinical outcome. HIF activity is regulated by an evolutionary conserved mechanism involving oxygen-dependent HIFa protein degradation. To identify novel components of the HIF pathway, we performed a genome-wide RNA interference screen in Caenorhabditis elegans, to suppress HIF-dependent phenotypes, like egg-laying defects and hypoxia survival. In addition to hif-1 (HIFa) and aha-1 (HIFb), we identified hlh-8, gska-3 and spe-8. The hlh-8 gene is homologous to the human oncogene TWIST1. We show that TWIST1 expression in human cancer cells is enhanced by hypoxia in a HIF-2a-dependent manner. Furthermore, intronic hypoxia response elements of TWIST1 are regulated by HIF-2a, but not HIF-1a. These results identify TWIST1 as a direct target gene of HIF-2a, which may provide insight into the acquired metastatic capacity of hypoxic tumors.

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Section: Cloning Plasmids and Rnaimentioning

confidence: 99%

The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2α

et al. 2007

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confidence: 99%

“…Hypoxia-inducible expression of transgenes has been reported in tumor cells and in cardiac myocytes. [4][5][6][7][8][9] Recently, new hypoxia-responsive vectors for tumor-specific gene therapy were developed. 10 Constructs containing five copies of HRE derived from the 5Ј-untranslated region of the human VEGF gene showed excellent transcriptional activation at low oxygen concentrations.…”

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confidence: 99%

Hypoxia-inducible transgene expression in differentiated human NT2N neurons – a cell culture model for gene therapy of postischemic neuronal loss

Cao

Shibata

2001

Gene Ther

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Expression of anti-apoptotic or neurotrophic transgene proteins in hypoxic neurons may provide a novel therapeutic strategy for neuroprotection and alleviation of damage to ischemic brain areas. NT2, a human neoplastic cell line which terminally differentiates into postmitotic neuronsIschemia of the brain due to major vessel thrombosis causes hypoxia in the respective vascular territory and subsequently induces neuronal death which is at least in part caused by apoptosis, especially in the penumbra of the lesion. 1,2 Hypoxia-inducible expression of anti-apoptotic or neurotrophic transgenes in hypoxic neurons may provide a novel therapeutic strategy for neuroprotection and alleviation of damage to ischemic brain areas.Hypoxia has been known as a potent inducer of a large number of genes including those encoding erythropoietin, vascular endothelial growth factor (VEGF), and some glycolytic enzymes, eg phosphoglycerate kinase. These genes have specific regulatory sequences in their promoter regions, known as hypoxia responsive elements (HRE). 3 Under hypoxic conditions, the upregulated hypoxia-inducible transcription factor 1 (HIF-1) binds to the HRE and initiates transcription of 3Ј sequences. This physiological mechanism has been utilized for develop- ment of hypoxia-responsive gene transfer vectors with HRE-based promoters. Hypoxia-inducible expression of transgenes has been reported in tumor cells and in cardiac myocytes. [4][5][6][7][8][9] Recently, new hypoxia-responsive vectors for tumor-specific gene therapy were developed. 10

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“…55 Regarding hypoxia-inducible promoters, VEGF promoter seems to enhance transcription more efficiently under hypoxic conditions than the erythropoietin promoter. 56 Endothelial transcription of GDEPT A number of viral vectors have used endothelial-specific transcription to deliver GDEPT-genes for destruction of tumor vasculature. Delivering HSV-TK/GCV therapy to tumor vasculature with different types of vectors has shown promising results.…”

Section: Transcriptional Targeting To Tumor Endotheliummentioning

confidence: 99%

Gene therapy targeting to tumor endothelium

2006

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Tumor-associated vasculature is a relatively accessible component of solid cancers that is essential for tumor survival and growth, providing a vulnerable target for cancer gene therapy administered by intravenous injection. Several features of tumor-associated vasculature are different from normal vasculature, including overexpression of receptors for angiogenic growth factors, markers of vasculogenesis, upregulation of coagulation cascades, aberrant expression of adhesion molecules and molecular consequences of hypoxia. Many of these differences provide candidate targets for tumor-selective 'transductional targeting' of genetically-or chemically modified vectors and upregulated gene expression can also enable 'transcriptional targeting', regulating tumor endothelia-selective expression of transgenes following nonspecific gene delivery. Tumor vasculature also represents an important site of therapeutic action by the secreted products of antiangiogenic gene therapies that are expressed in non-endothelial cells. In this review we assess the challenges faced and the vectors that may be suitable for gene delivery to exploit these targets. We also overview some of the strategies that have been developed to date and highlight the most promising areas of research.

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Enhancement of gene expression under hypoxic conditions using fragments of the human vascular endothelial growth factor and the erythropoietin genes

Cited by 87 publications

References 17 publications

The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2α

The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2α

Hypoxia-inducible transgene expression in differentiated human NT2N neurons – a cell culture model for gene therapy of postischemic neuronal loss

Gene therapy targeting to tumor endothelium

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