scholarly journals Differential signal pathway activation and 5-HT function: the role of gut enterochromaffin cells as oxygen sensors

2012 ◽  
Vol 303 (10) ◽  
pp. G1164-G1173 ◽  
Author(s):  
Martin Haugen ◽  
Rikard Dammen ◽  
Bernhard Svejda ◽  
Bjorn I. Gustafsson ◽  
Roswitha Pfragner ◽  
...  
Keyword(s):  
Tryptophan Hydroxylase ◽  
Cell Model ◽  
Hypoxia Inducible Factor ◽  
Mechanical Stretch ◽  
Renilla Luciferase ◽  
Low Oxygen ◽  
Differential Signal ◽  
Oxygen Levels ◽  
Ec Cells

The chemomechanosensory function of the gut enterochromaffin (EC) cell enables it to respond to dietary agents and mechanical stretch. We hypothesized that the EC cell, which also sensed alterations in luminal or mucosal oxygen level, was physiologically sensitive to fluctuations in O2. Given that low oxygen levels induce 5-HT production and secretion through a hypoxia inducible factor 1α (HIF-1α)-dependent pathway, we also hypothesized that increasing O2would reduce 5-HT production and secretion. Isolated normal EC cells as well as the well-characterized EC cell model KRJ-I were used to examine HIF signaling (luciferase-assays), hypoxia transcriptional response element (HRE)-mediated transcription (PCR), signaling pathways (Western blot), and 5-HT release (ELISA) during exposure to different oxygen levels. Normal EC cells and KRJ-I cells express HIF-1α, and transient transfection with Renilla luciferase under HRE control identified a hypoxia-mediated pathway in these cells. PCR confirmed activation of HIF-downstream targets, GLUT1, IGF2, and VEGF under reduced O2levels (0.5%). Reducing O2also elevated 5-HT secretion (2–3.2-fold) as well as protein levels of HIF-1α (1.7–3-fold). Increasing O2to 100% inhibited HRE-mediated signaling, transcription, reduced 5-HT secretion, and significantly lowered HIF-1α levels (∼75% of control). NF-κB signaling was also elevated during hypoxia (1.2–1.6-fold), but no significant changes were noted in PKA/cAMP. We concluded that gut EC cells are oxygen responsive, and alterations in O2levels differentially activate HIF-1α and tryptophan hydroxylase 1, as well as NF-κB signaling. This results in alterations in 5-HT production and secretion and identifies that the chemomechanosensory role of EC cells extends to oxygen sensing.

Apoptotic Cell Death Under Hypoxia

Physiology ◽  
2014 ◽  
Vol 29 (3) ◽  
pp. 168-176 ◽  
Author(s):  
Ataman Sendoel ◽  
Michael O. Hengartner
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Molecular Oxygen ◽  
Apoptotic Cell ◽  
Hypoxia Inducible Factor ◽  
Apoptotic Cell Death ◽  
Low Oxygen ◽  
Oxygen Levels

Eukaryotic life depends largely on molecular oxygen. During evolution, ingenious mechanisms have evolved that allow organisms to adapt when oxygen levels decrease. Many of these adaptional responses to low oxygen are orchestrated by the heterodimeric transcription factor hypoxia-inducible factor (HIF). Here, we review the link between HIF and apoptosis.

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

2007 ◽  
Vol 293 (1) ◽  
pp. C477-C485 ◽  
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.

scholarly journals Low Oxygen Stress During Early Development Influences Regulation of Hypoxia-Response Genes in Farmed Atlantic Salmon (Salmo salar)

2020 ◽  
Vol 10 (9) ◽  
pp. 3179-3188
Author(s):  
Tara Kelly ◽  
Hanne Johnsen ◽  
Erik Burgerhout ◽  
Helge Tveiten ◽  
Tina Thesslund ◽  
...  
Keyword(s):  
Atlantic Salmon ◽  
Early Development ◽  
Salmo Salar ◽  
Hypoxia Inducible Factor ◽  
Low Oxygen ◽  
Hypoxia Response ◽  
Oxygen Levels ◽  
Atlantic Salmon Salmo Salar ◽  
Natural Streams ◽  
Farmed Atlantic Salmon

Abstract Survival and growth of developing salmonids are negatively affected by low oxygen levels within gravel nests in natural streams, and hypoxic stress is often experienced by farmed Atlantic salmon (Salmo salar) within hatcheries. Exposure to hypoxia during early development may have long-lasting effects by altering epigenetic marks and gene expression in oxygen regulatory pathways. Here, we examine the transcriptomic response to low dissolved oxygen (DO) in post-hatch salmon reared continuously in 30%, 60% or 100% DO from fertilization until start of feeding. RNA sequencing revealed multiple differentially expressed genes, including oxygen transporting hemoglobin embryonic α subunit (hbae) and EGLN3 family hypoxia-inducible factor 3 (egln3) which regulates the stability of hypoxia inducible factor 1α (HIF-1α). Both hbae and egln3 displayed expression levels inversely correlated to oxygen concentration, and DNA methylation patterns within the egln3 promoter were negatively associated with the transcript levels. These results suggest that epigenetic processes are influenced by low oxygen levels during early development in Atlantic salmon to upregulate hypoxia-response genes.

Insights into The Function and Regulation of Jumonji C Lysine Demethylases as Hypoxic Responsive Enzymes

2020 ◽  
Vol 21 (7) ◽  
pp. 642-654
Author(s):  
Anand Chopra ◽  
Hemanta Adhikary ◽  
William G. Willmore ◽  
Kyle K. Biggar
Keyword(s):  
Catalytic Mechanism ◽  
Hypoxia Inducible Factor ◽  
Low Oxygen ◽  
Hypoxic Response ◽  
Protein Targets ◽  
Nonhistone Protein ◽  
Oxygen Sensitive ◽  
Demethylase Activity ◽  
Hypoxic Tumor

Cellular responses to hypoxia (low oxygen) are governed by oxygen sensitive signaling pathways. Such pathways, in part, are controlled by enzymes with oxygen-dependent catalytic activity, of which the role of prolyl 4-hydroxylases has been widely reviewed. These enzymes inhibit hypoxic response by inducing the oxygen-dependent degradation of hypoxia-inducible factor 1α, the master regulator of the transcriptional hypoxic response. Jumonji C domain-containing lysine demethylases are similar enzymes which share the same oxygen-dependent catalytic mechanism as prolyl 4- hydroxylases. Traditionally, the role of lysine demethylases has been studied in relation to demethylation activity against histone substrates, however, within the past decade an increasing number of nonhistone protein targets have been revealed, some of which have a key role in survival in the hypoxic tumor microenvironment. Within this review, we highlight the involvement of methyllysine in the hypoxic response with a focus on the HIF signaling pathway, the regulation of demethylase activity by oxygen, and provide insights into notable areas of future hypoxic demethylase research.

scholarly journals Hypoxia-Inducible Factor in Thyroid Carcinoma

2011 ◽  
Vol 2011 ◽  
pp. 1-17 ◽  
Author(s):  
Natalie Burrows ◽  
Muhammad Babur ◽  
Julia Resch ◽  
Kaye J. Williams ◽  
Georg Brabant
Keyword(s):  
Thyroid Carcinoma ◽  
Potential Role ◽  
Hypoxia Inducible Factor ◽  
Current Data ◽  
Low Oxygen ◽  
Expression Of Genes ◽  
Mitogen Activated Protein ◽  
Growth Factor Signalling ◽  
Pi3k Signalling

Intratumoural hypoxia (low oxygen tension) is associated with aggressive disease and poor prognosis. Hypoxia-inducible factor-1 is a transcription factor activated by hypoxia that regulates the expression of genes that promote tumour cell survival, progression, metastasis, and resistance to chemo/radiotherapy. In addition to hypoxia, HIF-1 can be activated by growth factor-signalling pathways such as the mitogen-activated protein kinases- (MAPK-) and phosphatidylinositol-3-OH kinases- (PI3K-) signalling cascades. Mutations in these pathways are common in thyroid carcinoma and lead to enhanced HIF-1 expression and activity. Here, we summarise current data that highlights the potential role of both hypoxia and MAPK/PI3K-induced HIF-1 signalling in thyroid carcinoma progression, metastatic characteristics, and the potential role of HIF-1 in thyroid carcinoma response to radiotherapy. Direct or indirect targeting of HIF-1 using an MAPK or PI3K inhibitor in combination with radiotherapy may be a new potential therapeutic target to improve the therapeutic response of thyroid carcinoma to radiotherapy and reduce metastatic burden.

scholarly journals Regeneration in Spinal Disease: Therapeutic Role of Hypoxia-Inducible Factor-1 Alpha in Regeneration of Degenerative Intervertebral Disc

2021 ◽  
Vol 22 (10) ◽  
pp. 5281
Author(s):  
Jin-Woo Kim ◽  
Neunghan Jeon ◽  
Dong-Eun Shin ◽  
So-Young Lee ◽  
Myongwhan Kim ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Structural Changes ◽  
Hypoxia Inducible Factor ◽  
Low Oxygen ◽  
Hypoxia Inducible Factor 1 ◽  
Metabolic Activities ◽  
Cartilaginous Endplate ◽  
Ivd Degeneration ◽  
Complex Joint

The intervertebral disc (IVD) is a complex joint structure comprising three primary components—namely, nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous endplate (CEP). The IVD retrieves oxygen from the surrounding vertebral body through CEP by diffusion and likely generates ATP via anaerobic glycolysis. IVD degeneration is characterized by a cascade of cellular, compositional, structural changes. With advanced age, pronounced changes occur in the composition of the disc extracellular matrix (ECM). NP and AF cells in the IVD possess poor regenerative capacity compared with that of other tissues. Hypoxia-inducible factor (HIF) is a master transcription factor that initiates a coordinated cellular cascade in response to a low oxygen tension environment, including the regulation of numerous enzymes in response to hypoxia. HIF-1α is essential for NP development and homeostasis and is involved in various processes of IVD degeneration process, promotes ECM in NP, maintains the metabolic activities of NP, and regulates dystrophic mineralization of NP, as well as angiogenesis, autophagy, and apoptosis during IVD degeneration. HIF-1α may, therefore, represent a diagnostic tool for early IVD degeneration and a therapeutic target for inhibiting IVD degeneration.

scholarly journals HIF1-alpha expressing cells induce a hypoxic-like response in neighbouring cancer cells

2018 ◽  
Author(s):  
Hannah Harrison ◽  
Henry J Pegg ◽  
Jamie Thompson ◽  
Christian Bates ◽  
Paul Shore
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Hypoxia Inducible Factor ◽  
Experimental Models ◽  
Metastatic Progression ◽  
Low Oxygen ◽  
Hypoxic Response ◽  
Oxygen Levels ◽  
Mammosphere Formation ◽  
Cellular Environment

AbstractHypoxia stimulates metastasis in cancer and is linked to poor patient prognosis. In tumours, oxygen levels vary and hypoxic regions exist within a generally well-oxygenated tumour. However, whilst the heterogeneous environment is known to contribute to metastatic progression, little is known about the mechanism by which heterogeneic hypoxia contributes to cancer progression. This is largely because existing experimental models do not recapitulate the heterogeneous nature of hypoxia. The primary effector of the hypoxic response is the transcription factor Hypoxia inducible factor 1-alpha (HIF1-alpha). HIF1-alpha is stabilised in response to low oxygen levels in the cellular environment and its expression is seen in hypoxic regions throughout the tumour.We have developed a model system in which HIF1-alpha can be induced within a sub-population of cancer cells, thus enabling us to mimic the effects of heterogeneic HIF1-alpha expression.We show that induction of HIF1-alpha not only recapitulates elements of the hypoxic response in the induced cells but also results in significant changes in proliferation, gene expression and mammosphere formation within the HIF1-alpha negative population.These findings suggest that the HIF1-alpha expressing cells found within hypoxic regions are likely to contribute to the subsequent progression of a tumour by modifying the behaviour of cells in the non-hypoxic regions of the local micro-environment.

scholarly journals Activation of Type 1 CRH Receptor Isoforms Induces Serotonin Release from Human Carcinoid BON-1N Cells: An Enterochromaffin Cell Model

Endocrinology ◽  
2011 ◽  
Vol 152 (1) ◽  
pp. 126-137 ◽  
Author(s):  
S. Vincent Wu ◽  
Pu-Qing Yuan ◽  
Jim Lai ◽  
Kelvin Wong ◽  
Monica C. Chen ◽  
...  
Keyword(s):  
Tryptophan Hydroxylase ◽  
Cell Function ◽  
Splice Variants ◽  
Cell Model ◽  
Serotonin Release ◽  
Intracellular Camp ◽  
Mrna Levels ◽  
Maximal Increase ◽  
Ec Cells

Abstract CRH and 5-hydroxytryptamine (5-HT) are expressed in human colonic enterochromaffin (EC) cells, but their interactions at the cellular level remain largely unknown. The mechanistic and functional relationship between CRH and 5-HT systems in EC cells was investigated in a human carcinoid cloned BON cell line (BON-1N), widely used as an in vitro model of EC cell function. First, we identified multiple CRH1 splice variants, including CRH1a, CRH1c, CRH1f, and a novel form lacking exon 4, designated here as CRH1i, in the BON-1N cells. The expression of CRH1i was also confirmed in human brain cortex, pituitary gland, and ileum. Immunocytochemistry and immunoblot analysis confirmed that BON-1N cells were CRH1 and 5-HT positive. CRH, urocortin (Ucn)-1, and cortagine, a selective CRH1 agonist, all increased intracellular cAMP, and this concentration-dependent response was inhibited by CRH1-selective antagonist NBI-35965. CRH and Ucn-1, but not Ucn-2, stimulated significant ERK1/2 phosphorylation. In transfected human embryonic kidney-293 cells, CRH1i isoforms produced a significant increase in pERK1/2 in response to CRH1 agonists that was sensitive to NBI-35965. CRH and Ucn-1 stimulated 5-HT release that reached a maximal increase of 3.3- and 4-fold at 10−8m over the basal level, respectively. In addition, exposure to CRH for 24-h up-regulated tryptophan hydroxylase-1 mRNA levels in the BON-1N cells. These findings define the expression of EC cell-specific CRH1 isoforms and activation of CRH1-dependent pathways leading to 5-HT release and synthesis; thus, providing functional evidence of a link exists between CRH and 5-HT systems, which have implications in stress-induced CRH1 and 5-HT-mediated stimulation of lower intestinal function.

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

2013 ◽  
Vol 83 (3) ◽  
pp. 188-197 ◽  
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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