Induction of glucose transporter 1 expression through hypoxia-inducible factor 1α under hypoxic conditions in trophoblast-derived cells

Glucose transporter 1 (GLUT1) plays an important role in the transport of glucose in the placenta. During early pregnancy, placentation occurs in a relatively hypoxic environment that is essential for appropriate embryonic development, and GLUT1 expression is enhanced in response to oxygen deficiency in the placenta. Hypoxia-inducible factor-1 (HIF-1)α is involved in the induction of GLUT1 expression in other cells. The present study was designed to test whether HIF-1α is involved in hypoxia-induced activation of GLUT1 expression using trophoblast-derived human BeWo and rat Rcho-1 cells as models. GLUT1 mRNA and protein expression were elevated under 5% O2 or in the presense of cobalt chloride, which has been shown to mimic hypoxia. Using rat GLUT1 (rGLUT1) promoter–luciferase constructs, we showed that this up-regulation was mediated at the transcriptional level. Deletion mutant analysis of the rGLUT1 promoter indicated that a 184 bp hypoxia-responsive element (HRE) of the promoter was essential to increase GLUT1 reporter gene expression in response to low-oxygen conditions. BeWo and Rcho-1 cells cultured under 5% O2 or with CoCl2 showed increased expression of HIF-1α protein compared with those cultured under 20% O2. To test whether this factor is directly involved in hypoxia-induced GLUT1 promoter activation, BeWo and Rcho-1 cells were transiently transfected with an HIF-1α expression vector. Exogeneous HIF-1α markedly increased the GLUT1 promoter activity from constructs containing the HRE site, while the GLUT1 promoter constructs lacking the HRE site were not activated by exogenous HIF-1α These data demonstrate that GLUT1 is up-regulated under 5% O2 or in the presence of CoCl2 in the placental cell lines through HIF-1α interaction with a consensus HRE site of the GLUT1 promoter.

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HIF1-α-Mediated Gene Expression Induced by Vitamin B1 Deficiency

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000159 ◽

2013 ◽

Vol 83 (3) ◽

pp. 188-197 ◽

Cited By ~ 21

Author(s):

Rebecca L. Sweet ◽

Jason A. Zastre

Keyword(s):

Gene Expression ◽

Thiamine Deficiency ◽

Glucose Transporter ◽

Neuroblastoma Cell ◽

Hypoxia Inducible Factor ◽

Clinical Manifestations ◽

Vitamin B1 ◽

Low Oxygen ◽

Glucose Transporter 1 ◽

Metabolic Intermediates

It is well established that thiamine deficiency results in an excess of metabolic intermediates such as lactate and pyruvate, which is likely due to insufficient levels of cofactor for the function of thiamine-dependent enzymes. When in excess, both pyruvate and lactate can increase the stabilization of the hypoxia-inducible factor 1-alpha (HIF-1α) transcription factor, resulting in the trans-activation of HIF-1α regulated genes independent of low oxygen, termed pseudo-hypoxia. Therefore, the resulting dysfunction in cellular metabolism and accumulation of pyruvate and lactate during thiamine deficiency may facilitate a pseudo-hypoxic state. In order to investigate the possibility of a transcriptional relationship between hypoxia and thiamine deficiency, we measured alterations in metabolic intermediates, HIF-1α stabilization, and gene expression. We found an increase in intracellular pyruvate and extracellular lactate levels after thiamine deficiency exposure to the neuroblastoma cell line SK-N-BE. Similar to cells exposed to hypoxia, there was a corresponding increase in HIF-1α stabilization and activation of target gene expression during thiamine deficiency, including glucose transporter-1 (GLUT1), vascular endothelial growth factor (VEGF), and aldolase A. Both hypoxia and thiamine deficiency exposure resulted in an increase in the expression of the thiamine transporter SLC19A3. These results indicate thiamine deficiency induces HIF-1α-mediated gene expression similar to that observed in hypoxic stress, and may provide evidence for a central transcriptional response associated with the clinical manifestations of thiamine deficiency.

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Hypoxic upregulation of glucose transporters in BeWo choriocarcinoma cells is mediated by hypoxia-inducible factor-1

AJP Cell Physiology ◽

10.1152/ajpcell.00075.2007 ◽

2007 ◽

Vol 293 (1) ◽

pp. C477-C485 ◽

Cited By ~ 78

Author(s):

Marc U. Baumann ◽

Stacy Zamudio ◽

Nicholas P. Illsley

Keyword(s):

Glucose Transport ◽

Oxygen Tension ◽

Glucose Transporter ◽

Cell Model ◽

Hypoxia Inducible Factor ◽

Trophoblast Cell ◽

Low Oxygen ◽

Bewo Cells ◽

Glut1 Expression ◽

Choriocarcinoma Cells

Placental hypoxia has been implicated in pregnancy pathologies, including fetal growth restriction and preeclampsia; however, the mechanism by which the trophoblast cell responds to hypoxia has not been adequately explored. Glucose transport, a process crucial to fetoplacental growth, is upregulated by hypoxia in a number of cell types. We investigated the effects of hypoxia on the regulation of trophoblast glucose transporter (GLUT) expression and activity in BeWo choriocarcinoma cells, a trophoblast cell model, and human placental villous tissue explants. GLUT1 expression in BeWo cells was upregulated by the hypoxia-inducing chemical agents desferroxamine and cobalt chloride. Reductions in oxygen tension resulted in dose-dependent increases in GLUT1 and GLUT3 expression. Exposure of cells to hypoxic conditions also resulted in an increase in transepithelial glucose transport. A role for hypoxia-inducible factor (HIF)-1 was suggested by the increase in HIF-1α as a result of hypoxia and by the increase in GLUT1 expression following treatment of BeWo with MG-132, a proteasomal inhibitor that increases HIF-1 levels. The function of HIF-1 was confirmed in experiments where the hypoxic upregulation of GLUT1 and GLUT3 was inhibited by antisense HIF-1α. In contrast to BeWo cells, hypoxia produced minimal increases in GLUT1 expression in explants; however, treatment with MG-132 did upregulate syncytial basal membrane GLUT1. Our results show that GLUTs are upregulated by hypoxia via a HIF-1-mediated pathway in trophoblast cells and suggest that the GLUT response to hypoxia in vivo will be determined not only by low oxygen tension but also by other factors that modulate HIF-1 levels.

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Transcriptome sequencing revealed differences in the response of renal cancer cells to hypoxia and CoCl2 treatment

F1000Research ◽

10.12688/f1000research.7571.1 ◽

2015 ◽

Vol 4 ◽

pp. 1518 ◽

Cited By ~ 9

Author(s):

Nadezhda Zhigalova ◽

Artem Artemov ◽

Alexander M. Mazur ◽

Egor B. Prokhortchouk

Keyword(s):

Cancer Cells ◽

Human Cancer ◽

Hypoxia Inducible Factor ◽

Low Oxygen ◽

Human Cancer Cells ◽

Hypoxic Conditions ◽

Pathway Activation ◽

Oxygen Conditions ◽

Order Of Magnitude ◽

Transcriptional Changes

Human cancer cells are subjected to hypoxic conditions in many tumours. Hypoxia causes alterations in the glycolytic pathway activation through stabilization of hypoxia-inducible factor 1. Currently, two approaches are commonly used to model hypoxia: an alternative to generating low-oxygen conditions in an incubator, cells can be treated with CoCl2. We performed RNA-seq experiments to study transcriptomes of human Caki-1 cells under real hypoxia and after CoCl2 treatment. Despite causing transcriptional changes of a much higher order of magnitude for the genes in the hypoxia regulation pathway, CoCl2 treatment fails to induce alterations in the glycolysis / gluconeogenesis pathway. Moreover, CoCl2 caused aberrant activation of other oxidoreductases in glycine, serine and threonine metabolism pathways.

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SQAP, an acyl sulfoquinovosyl derivative, suppresses expression of histone deacetylase and induces cell death of cancer cells under hypoxic conditions

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbaa015 ◽

2021 ◽

Vol 85 (1) ◽

pp. 85-91

Author(s):

Hirofumi Kawakubo ◽

Shinji Kamisuki ◽

Kei Suzuki ◽

Jesus Izaguirre-Carbonell ◽

Shiki Saito ◽

...

Keyword(s):

Histone Deacetylase ◽

Biological Activities ◽

Hypoxia Inducible Factor ◽

Hdac Inhibitors ◽

Low Oxygen ◽

Hypoxic Conditions ◽

Oxygen Conditions ◽

Model Mouse ◽

Hepatocarcinoma Cells ◽

Hepatoma Model

Abstract Sulfoglycolipid, SQAP, is a radiosensitizing agent that makes tumor cells more sensitive to radiation therapy. A previous study revealed that SQAP induced the degradation of hypoxia-inducible factor-1α (HIF-1α) and inhibited angiogenesis in a hepatoma model mouse. Herein, we examined the biological activities of SQAP against hepatocarcinoma cells under low oxygen conditions. Cell growth inhibition of SQAP under hypoxic conditions was significantly higher than that under normoxic conditions. In addition, SQAP was found to impair the expression of histone deacetylase (HDAC) under low oxygen conditions. Our present data suggested that SQAP induced the degradation of HIF-1α and then decreased the expression of HDAC1. Unlike known HDAC inhibitors, SQAP increased the acetylation level of histone in cells without inhibition of enzymatic activity of HDACs. Our data demonstrated hypoxia-specific unique properties of SQAP.

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Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1α

Blood ◽

10.1182/blood-2003-07-2427 ◽

2004 ◽

Vol 103 (3) ◽

pp. 1124-1130 ◽

Cited By ~ 290

Author(s):

Caroline C. Blouin ◽

Elisabeth L. Pagé ◽

Guylaine M. Soucy ◽

Darren E. Richard

Keyword(s):

Wound Healing ◽

Glucose Transporter ◽

Hypoxia Inducible Factor ◽

Gene Activation ◽

Dominant Negative ◽

Binding Motif ◽

Mrna Levels ◽

Low Oxygen ◽

Glucose Transporter 1 ◽

Hypoxic Induction

AbstractHypoxia-inducible factor 1 (HIF-1) regulates many genes induced by low oxygen conditions. The expression of important hypoxic genes such as glucose transporter 1 and vascular endothelial growth factor are increased in macrophages during wound healing and in the presence of the endotoxin, lipopolysaccharide (LPS). Recent studies have demonstrated that nonhypoxic stimuli can also activate HIF-1 in a cell-specific manner. Here, we demonstrate that in macrophages, LPS can control the activation of hypoxia-regulated genes through the HIF-1 pathway. We show that in these cells, protein expression levels of HIF-1α are strongly increased to levels comparable to hypoxic induction. HIF-1α mRNA levels are markedly increased following LPS stimulation, suggesting a transcriptional induction. In functional studies, the LPS-induced HIF-1 complex could specifically bind to the HIF-1 DNA-binding motif. Additionally, when cells were transfected with an HIF-1-specific reporter construct, LPS could strongly activate the expression of the reporter to levels that surpassed those observed after hypoxic induction. This induction was blocked by the cotransfection of a dominant-negative form of HIF-1α. These results indicate that the HIF-1 complex is involved in macrophage gene activation following LPS exposure and identify a novel pathway that could play a determinant role during inflammation and wound healing. (Blood. 2004;103:1124-1130)

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Hypoxia-Induced Gene Expression Occurs Solely through the Action of Hypoxia-Inducible Factor 1α (HIF-1α): Role of Cytoplasmic Trapping of HIF-2α

Molecular and Cellular Biology ◽

10.1128/mcb.23.14.4959-4971.2003 ◽

2003 ◽

Vol 23 (14) ◽

pp. 4959-4971 ◽

Cited By ~ 115

Author(s):

Sang-ki Park ◽

Agnes M. Dadak ◽

Volker H. Haase ◽

Lucrezia Fontana ◽

Amato J. Giaccia ◽

...

Keyword(s):

Gene Expression ◽

Transcriptional Activity ◽

Hypoxia Inducible Factor ◽

Low Oxygen ◽

Hypoxic Conditions ◽

Show Evidence ◽

Dependent Protein ◽

A Cell ◽

Cell Type Specific ◽

Inducible Genes

ABSTRACT The hypoxia-inducible factors 1α (HIF-1α) and 2α (HIF-2α) have extensive structural homology and have been identified as key transcription factors responsible for gene expression in response to hypoxia. They play critical roles not only in normal development, but also in tumor progression. Here we report on the differential regulation of protein expression and transcriptional activity of HIF-1α and -2α by hypoxia in immortalized mouse embryo fibroblasts (MEFs). We show that oxygen-dependent protein degradation is restricted to HIF-1α, as HIF-2α protein is detected in MEFs regardless of oxygenation and is localized primarily to the cytoplasm. Endogenous HIF-2α remained transcriptionally inactive under hypoxic conditions; however, ectopically overexpressed HIF-2α translocated into the nucleus and could stimulate expression of hypoxia-inducible genes. We show that the factor inhibiting HIF-1 can selectively inhibit the transcriptional activity of HIF-1α but has no effect on HIF-2α-mediated transcription in MEFs. We propose that HIF-2α is not a redundant transcription factor of HIF-1α for hypoxia-induced gene expression and show evidence that there is a cell type-specific modulator(s) that enables selective activation of HIF-1α but not HIF-2α in response to low-oxygen stress.

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Looking beyond stratification: a model-based analysis of the biological drivers of oxygen deficiency in the North Sea

Biogeosciences ◽

10.5194/bg-13-2511-2016 ◽

2016 ◽

Vol 13 (8) ◽

pp. 2511-2535 ◽

Cited By ~ 21

Author(s):

Fabian Große ◽

Naomi Greenwood ◽

Markus Kreus ◽

Hermann-Josef Lenhart ◽

Detlev Machoczek ◽

...

Keyword(s):

North Sea ◽

Oxygen Deficiency ◽

Low Oxygen ◽

The North ◽

Oxygen Conditions ◽

Southern Central ◽

The North Sea ◽

Central North Sea ◽

The Impact ◽

Oxygen Dynamics

Abstract. Low oxygen conditions, often referred to as oxygen deficiency, occur regularly in the North Sea, a temperate European shelf sea. Stratification represents a major process regulating the seasonal dynamics of bottom oxygen, yet, lowest oxygen conditions in the North Sea do not occur in the regions of strongest stratification. This suggests that stratification is an important prerequisite for oxygen deficiency, but that the complex interaction between hydrodynamics and the biological processes drives its evolution. In this study we use the ecosystem model HAMSOM-ECOHAM to provide a general characterisation of the different zones of the North Sea with respect to oxygen, and to quantify the impact of the different physical and biological factors driving the oxygen dynamics inside the entire sub-thermocline volume and directly above the bottom. With respect to oxygen dynamics, the North Sea can be subdivided into three different zones: (1) a highly productive, non-stratified coastal zone, (2) a productive, seasonally stratified zone with a small sub-thermocline volume, and (3) a productive, seasonally stratified zone with a large sub-thermocline volume. Type 2 reveals the highest susceptibility to oxygen deficiency due to sufficiently long stratification periods (>  60 days) accompanied by high surface productivity resulting in high biological consumption, and a small sub-thermocline volume implying both a small initial oxygen inventory and a strong influence of the biological consumption on the oxygen concentration. Year-to-year variations in the oxygen conditions are caused by variations in primary production, while spatial differences can be attributed to differences in stratification and water depth. The large sub-thermocline volume dominates the oxygen dynamics in the northern central and northern North Sea and makes this region insusceptible to oxygen deficiency. In the southern North Sea the strong tidal mixing inhibits the development of seasonal stratification which protects this area from the evolution of low oxygen conditions. In contrast, the southern central North Sea is highly susceptible to low oxygen conditions (type 2). We furthermore show that benthic diagenetic processes represent the main oxygen consumers in the bottom layer, consistently accounting for more than 50 % of the overall consumption. Thus, primary production followed by remineralisation of organic matter under stratified conditions constitutes the main driver for the evolution of oxygen deficiency in the southern central North Sea. By providing these valuable insights, we show that ecosystem models can be a useful tool for the interpretation of observations and the estimation of the impact of anthropogenic drivers on the North Sea oxygen conditions.

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Acute exercise increases brain region-specific expression of MCT1, MCT2, MCT4, GLUT1, and COX IV proteins

Journal of Applied Physiology ◽

10.1152/japplphysiol.01288.2013 ◽

2014 ◽

Vol 116 (9) ◽

pp. 1238-1250 ◽

Cited By ~ 39

Author(s):

Masaki Takimoto ◽

Taku Hamada

Keyword(s):

Brain Region ◽

Acute Exercise ◽

Glucose Transporter ◽

Prolonged Exercise ◽

Ketone Bodies ◽

Hypoxia Inducible Factor ◽

Exercise Session ◽

Specific Expression ◽

Glucose Transporter 1 ◽

The Brain

The brain is capable of oxidizing lactate and ketone bodies through monocarboxylate transporters (MCTs). We examined the protein expression of MCT1, MCT2, MCT4, glucose transporter 1 (GLUT1), and cytochrome- c oxidase subunit IV (COX IV) in the rat brain within 24 h after a single exercise session. Brain samples were obtained from sedentary controls and treadmill-exercised rats (20 m/min, 8% grade). Acute exercise resulted in an increase in lactate in the cortex, hippocampus, and hypothalamus, but not the brainstem, and an increase in β-hydroxybutyrate in the cortex alone. After a 2-h exercise session MCT1 increased in the cortex and hippocampus 5 h postexercise, and the effect lasted in the cortex for 24 h postexercise. MCT2 increased in the cortex and hypothalamus 5–24 h postexercise, whereas MCT2 increased in the hippocampus immediately after exercise, and remained elevated for 10 h postexercise. Regional upregulation of MCT2 after exercise was associated with increases in brain-derived neurotrophic factor and tyrosine-related kinase B proteins, but not insulin-like growth factor 1. MCT4 increased 5–10 h postexercise only in the hypothalamus, and was associated with increased hypoxia-inducible factor-1α expression. However, none of the MCT isoforms in the brainstem was affected by exercise. Whereas GLUT 1 in the cortex increased only at 18 h postexercise, COX IV in the hippocampus increased 10 h after exercise and remained elevated for 24 h postexercise. These results suggest that acute prolonged exercise induces the brain region-specific upregulation of MCT1, MCT2, MCT4, GLUT1, and COX IV proteins.

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Jasus lalandii 'walkouts' or mass strandings in South Africa during the 1990s: an overview

Marine and Freshwater Research ◽

10.1071/mf01100 ◽

2001 ◽

Vol 52 (8) ◽

pp. 1085 ◽

Cited By ~ 47

Author(s):

Andrew C. Cockcroft

Keyword(s):

South Africa ◽

West Coast ◽

The Other ◽

Fishing Industry ◽

Low Oxygen ◽

Rock Lobster ◽

The West ◽

Hypoxic Conditions ◽

Oxygen Conditions ◽

Mass Mortalities

Faunal mass mortalities are a sporadic, but not uncommon, feature of the West and South coasts of South Africa. Five mass mortalities of West Coast rock lobsterJasus lalandii, including three of the most severe ever recorded in South Africa, occurred in the 1990s and resulted in the stranding of about 2263 tonnes of lobster. The bulk (97%) of the loss occurred in the last three years of the decade. The five events occurred within an 80 km stretch of coastline that straddled two fishing zones and resulted from hypoxic conditions associated with highbiomass dinoflagellate blooms. In each case, the quantity of lobsters stranded was directly related to the extent or duration of low-oxygen conditions. Small females constituted the bulk of the lobster stranded in most events. The lobster fisheries in the affected fishing zones suffered severe impacts. Recovery in one zone appears to be extremely slow, whereas the other zone is more resilient. Not only would a continuation of the trend of increasing frequency and severity of lobster strandings devastate the rock-lobster fishing industry and the employment prospects of small fishing communities, but it could also seriously affect the ecology of the region.

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