Oxygen sensing and signaling: impact on the regulation of physiologically important genes

Zhu, Hao; Bunn, H. Franklin

doi:10.1016/s0034-5687(99)00024-9

Cited by 151 publications

(105 citation statements)

References 63 publications

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“…A cytosolic flavoheme protein acts as an oxygen sensor that detects decreased oxygen tension and activates transcription factors through signal transduction pathways. 153,154 Hypoxia inducible factor 1 (HIF-1) is a major transcription factor. 155 The activation of HIF-1 depends upon signaling-dependent rescue of its alphasubunit from oxygen-dependent degradation in the proteasome and formation of a heterodimer with HIF1beta, which then translocates to the nucleus and impacts on the transcription of genes that are upregulated by hypoxia [156][157][158] Activation of HIF-1 has been shown to increase production of a variety of factors implicated in the pathogenesis of diabetic retinopathy (eg ischaemic retina 159 ).…”

Section: Leukocyte Activation and Adherencementioning

confidence: 99%

The pathogenesis of diabetic retinopathy: old concepts and new questions

Cai

Boulton

2002

Eye

294

196

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Hyperglycaemia appears to be a critical factor in the aetiology of diabetic retinopathy and initiates downstream events including: basement membrane thickening, pericyte drop out and retinal capillary non-perfusion. More recently, focus has been directed to the molecular basis of the disease process in diabetic retinopathy. Of particular importance in the development and progression of diabetic retinopathy is the role of growth factors (eg vascular endothelial growth factor, placenta growth factor and pigment epithelium-derived factor) together with specific receptors and obligate components of the signal transduction pathway needed to support them. Despite these advances there are still a number of important questions that remain to be answered before we can confidently target pathological signals. How does hyperglycaemia regulate retinal vessels? Which growth factors are most important and at what stage of retinopathy do they operate? What is the preferred point in the growth factor signalling cascade for therapeutic intervention? Answers to these questions will provide the basis for new therapeutic interventions in a debilitating ocular condition.

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Section: Leukocyte Activation and Adherencementioning

confidence: 99%

The pathogenesis of diabetic retinopathy: old concepts and new questions

Cai

Boulton

2002

Eye

294

196

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“…In hypoxic conditions (1% O 2 , 1-6 h), the mRNA level of HIF-1a, Egr-1 and MTF-1 increased significantly in HeLa and C2C12 cells (Table 2), which is consistent with the data published by others. 8,10,18 We next tested whether the increased expression of each transcription factor translates into increased binding to its target DNA motif. Gel shift assays with the nuclear extracts prepared in both normoxic and hypoxic conditions …”

Section: Validation In Different Cells and With Other Cdnasmentioning

confidence: 99%

“…17 These hypoxia mimetics are thought to exploit the cellular oxygensensing mechanism and the hypoxic signal-transduction pathway that lead to stimulation of several hypoxiaresponsive genes. 18 In the present study, we hypothesized that combinations of the HRE, MRE and Egr-1-binding site (EBS) might provide novel means by which to enhance the level of hypoxic induction and to control target gene expression with hypoxia mimetics. Once successful, such chimeric enhancer vectors could rigorously restrict therapeutic gene expression to hypoxia-or hypoxia mimetics-enriched tissues, thereby providing greatly enhanced condition-specific expression.…”

Section: Introductionmentioning

confidence: 99%

A novel chimeric promoter that is highly responsive to hypoxia and metals

et al. 2006

Gene Ther

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To develop a potent hypoxia-inducible promoter, we evaluated the usefulness of chimeric combinations of the (Egr-1)-binding site (EBS) from the Egr-1 gene, the metal-response element (MRE) from the metallothionein gene, and the hypoxia-response element (HRE) from the phosphoglycerate kinase 1 gene. In transient transfection assays, combining three copies of HRE (3 Â HRE) with either EBS or MRE significantly increased hypoxia responsiveness. When a three-enhancer combination was tested, the EBS-MRE-3 Â HRE (E-M-H) gave a hypoxia induction ratio of 69. The expression induced from E-M-H-pGL3 was 2.4-fold higher than that induced from H-pGL3 and even surpassed the expression from a human cytomegalovirus promoter-driven vector. The high inducibility of E-M-H was confirmed by validation studies in different cells and by expressing other cDNAs. Gel shift assays together with functional overexpression studies suggested that increased levels of hypoxiainducible factor 1a, metal transcription factor-1 and Egr-1 may be associated with the high inducibility of the E-M-H chimeric promoter. E-M-H was also induced by hypoxia mimetics such as Co 2+ and deferoxamine (DFX) and by hydrogen peroxide. Gene expression from the E-M-H was reversible as shown by the reduced expression of the transgene upon removal of inducers such as hypoxia and DFX. In vivo evaluation of the E-M-H in ischemic muscle revealed that erythropoietin secretion and luciferase and LacZ expression were significantly higher in the E-M-H group than in a control or H group. With its high induction capacity and versatile means of modulation, this novel chimeric promoter should find wide application in the treatment of ischemic diseases and cancer.

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“…16,17 Specific hypoxia-responsive elements (HRE) have been cloned and employed for expression of therapeutic transgenes in hypoxic tumor cells. 4,9,18 Using HRE from the mouse phosphoglycerate kinase 1 gene (pgk1) to drive expression of cytosine deaminase (CD), Dachs et al 4 demonstrated that CD was induced 6.8-fold under hypoxic conditions and caused tumor cell killing when the prodrug 5-fluocytosine (5-FC) was administered.…”

Section: Units (Rlu)/mg Protein) Control Nt2 Cells Transfected With mentioning

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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Oxygen sensing and signaling: impact on the regulation of physiologically important genes

Cited by 151 publications

References 63 publications

The pathogenesis of diabetic retinopathy: old concepts and new questions

The pathogenesis of diabetic retinopathy: old concepts and new questions

A novel chimeric promoter that is highly responsive to hypoxia and metals

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

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