scholarly journals Oxygen Sensing and Viral Replication: Implications for Tropism and Pathogenesis

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1213
Author(s):  
Peter Jianrui Liu ◽  
Peter Balfe ◽  
Jane A McKeating ◽  
Mirjam Schilling
Keyword(s):  
Oxygen Tension ◽  
Cellular Response ◽  
Viral Infections ◽  
Oxygen Sensing ◽  
Treatment Options ◽  
Hypoxia Inducible Factor ◽  
Low Oxygen ◽  
Pharmaceutical Agents ◽  
Hif Pathway ◽  
Essential Prerequisite

The ability to detect and respond to varying oxygen tension is an essential prerequisite to life. Several mechanisms regulate the cellular response to oxygen including the prolyl hydroxylase domain (PHD)/factor inhibiting HIF (FIH)-hypoxia inducible factor (HIF) pathway, cysteamine (2-aminoethanethiol) dioxygenase (ADO) system, and the lysine-specific demethylases (KDM) 5A and KDM6A. Using a systems-based approach we discuss the literature on oxygen sensing pathways in the context of virus replication in different tissues that experience variable oxygen tension. Current information supports a model where the PHD-HIF pathway enhances the replication of viruses infecting tissues under low oxygen, however, the reverse is true for viruses with a selective tropism for higher oxygen environments. Differences in oxygen tension and associated HIF signaling may play an important role in viral tropism and pathogenesis. Thus, pharmaceutical agents that modulate HIF activity could provide novel treatment options for viral infections and associated pathological conditions.

scholarly journals Loss of the HIF pathway in a widely distributed intertidal crustacean, the copepodTigriopus californicus

2019 ◽  
Vol 116 (26) ◽  
pp. 12913-12918 ◽  
Author(s):  
Allie M. Graham ◽  
Felipe S. Barreto
Keyword(s):  
Oxygen Sensing ◽  
Phylogenetic Analyses ◽  
Hypoxia Inducible Factor ◽  
Small Animal ◽  
Gene Families ◽  
Regulatory Elements ◽  
Low Oxygen ◽  
Cellular Mechanisms ◽  
Genetic Components ◽  
Hif Pathway

Hypoxia is a major physiological constraint for which multicellular eukaryotes have evolved robust cellular mechanisms capable of addressing dynamic changes in O2availability. In animals, oxygen sensing and regulation is primarily performed by the hypoxia-inducible factor (HIF) pathway, and the key components of this pathway are thought to be highly conserved across metazoans. Marine intertidal habitats are dynamic environments, and their inhabitants are known to tolerate wide fluctuations in salinity, temperature, pH, and oxygen. In this study, we show that an abundant intertidal crustacean, the copepodTigriopus californicus, has lost major genetic components of the HIF pathway, but still shows robust survivorship and transcriptional response to hypoxia. Mining of protein domains across the genome, followed by phylogenetic analyses of gene families, did not identify two key regulatory elements of the metazoan hypoxia response, namely the transcription factorHIF-α and its oxygen-sensing prolyl hydroxylase repressor,EGLN. Despite this loss, phenotypic assays revealed that this species is tolerant to extremely low levels of available O2for at least 24 h at both larval and adult stages. RNA-sequencing (seq) of copepods exposed to nearly anoxic conditions showed differential expression of over 400 genes, with evidence for induction of glycolytic metabolism without a depression of oxidative phosphorylation. Moreover, genes involved in chitin metabolism and cuticle reorganization show categorically a consistent pattern of change during anoxia, highlighting this pathway as a potential solution to low oxygen availability in this small animal with no respiratory structures or pigment.

Independent Losses of the Hypoxia-Inducible Factor (HIF) Pathway within Crustacea

2020 ◽  
Vol 37 (5) ◽  
pp. 1342-1349 ◽  
Author(s):  
Allie M Graham ◽  
Felipe S Barreto
Keyword(s):  
Cellular Response ◽  
Phylogenetic Analyses ◽  
Hypoxia Inducible Factor ◽  
Gene Families ◽  
Hypoxic Stress ◽  
Group Level ◽  
Low Oxygen ◽  
Transcriptomic Data ◽  
Cellular Oxygen ◽  
Hif Pathway

Abstract Metazoans respond to hypoxic stress via the hypoxia-inducible factor (HIF) pathway, a mechanism thought to be extremely conserved due to its importance in monitoring cellular oxygen levels and regulating responses to hypoxia. However, recent work revealed that key members of the HIF pathway have been lost in specific lineages (a tardigrade and a copepod), suggesting that this pathway is not as widespread in animals as previously assumed. Using genomic and transcriptomic data from 70 different species across 12 major crustacean groups, we assessed the degree to which the gene HIFα, the master regulator of the HIF pathway, was conserved. Mining of protein domains, followed by phylogenetic analyses of gene families, uncovered group-level losses of HIFα, including one across three orders within Cirripedia, and in three orders within Copepoda. For these groups, additional assessment showed losses of HIF repression machinery (EGLN and VHL). These results suggest the existence of alternative mechanisms for cellular response to low oxygen and highlight these taxa as models useful for probing these evolutionary outcomes.

scholarly journals Variations within oxygen-regulated gene expression in humans

2009 ◽  
Vol 106 (1) ◽  
pp. 212-220 ◽  
Author(s):  
Jerome T. S. Brooks ◽  
Gareth P. Elvidge ◽  
Louisa Glenny ◽  
Jonathan M. Gleadle ◽  
Chun Liu ◽  
...  
Keyword(s):  
Cellular Response ◽  
Genetic Manipulation ◽  
Hypoxia Inducible Factor ◽  
Hereditary Disease ◽  
Peripheral Blood Lymphocytes ◽  
Cellular Level ◽  
Normal Individuals ◽  
Regulated Gene Expression ◽  
Open Question ◽  
Hif Pathway

The effects of hypoxia on gene transcription are mainly mediated by a transcription factor complex termed hypoxia-inducible factor (HIF). Genetic manipulation of animals and studies of humans with rare hereditary disease have shown that modifying the HIF pathway affects systems-level physiological responses to hypoxia. It is, however, an open question whether variations in systems-level responses to hypoxia between individuals could arise from variations within the HIF system. This study sought to determine whether variations in the responsiveness of the HIF system at the cellular level could be detected between normal individuals. Peripheral blood lymphocytes (PBL) were isolated on three separate occasions from each of 10 healthy volunteers. After exposure of PBL to eight different oxygen tensions ranging from 20% to 0.1%, the expression levels of four HIF-regulated transcripts involved in different biological pathways were measured. The profile of expression of all four transcripts in PBL was related to oxygen tension in a curvilinear manner. Double logarithmic transformation of these data resulted in a linear relationship that allowed the response to be parameterized through a gradient and intercept. Analysis of variance (ANOVA) on these parameters showed that the level of between-subject variation in the gradients of the responses that was common across all four HIF-regulated transcripts was significant ( P = 0.008). We conclude that statistically significant variation within the cellular response to hypoxia can be detected between normal humans. The common nature of the variability across all four HIF-regulated genes suggests that the source of this variation resides within the HIF system itself.

scholarly journals Hypoxia-inducible factor–1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma

2014 ◽  
Vol 37 (6) ◽  
pp. E8 ◽  
Author(s):  
Matthew Womeldorff ◽  
David Gillespie ◽  
Randy L. Jensen
Keyword(s):  
Cellular Response ◽  
Treatment Options ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Poor Patient ◽  
Growth Development ◽  
The Relationship ◽  
Insight Into ◽  
Upstream Regulators

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1–regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

scholarly journals Hypoxia-Inducible Factor 1α Is Essential for Cell Cycle Arrest during Hypoxia

2003 ◽  
Vol 23 (1) ◽  
pp. 359-369 ◽  
Author(s):  
Nobuhito Goda ◽  
Heather E. Ryan ◽  
Bahram Khadivi ◽  
Wayne McNulty ◽  
Robert C. Rickert ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cell Cycle Arrest ◽  
Cellular Response ◽  
Hypoxia Inducible Factor ◽  
Growth Arrest ◽  
Cell Types ◽  
Low Oxygen ◽  
Double Knockout ◽  
Cycle Arrest

ABSTRACT A classical cellular response to hypoxia is a cessation of growth. Hypoxia-induced growth arrest differs in different cell types but is likely an essential aspect of the response to wounding and injury. An important component of the hypoxic response is the activation of the hypoxia-inducible factor 1 (HIF-1) transcription factor. Although this transcription factor is essential for adaptation to low oxygen levels, the mechanisms through which it influences cell cycle arrest, including the degree to which it cooperates with the tumor suppressor protein p53, remain poorly understood. To determine broadly relevant aspects of HIF-1 function in primary cell growth arrest, we examined two different primary differentiated cell types which contained a deletable allele of the oxygen-sensitive component of HIF-1, the HIF-1α gene product. The two cell types were murine embryonic fibroblasts and splenic B lymphocytes; to determine how the function of HIF-1α influenced p53, we also created double-knockout (HIF-1α null, p53 null) strains and cells. In both cell types, loss of HIF-1α abolished hypoxia-induced growth arrest and did this in a p53-independent fashion. Surprisingly, in all cases, cells lacking both p53 and HIF-1α genes have completely lost the ability to alter the cell cycle in response to hypoxia. In addition, we have found that the loss of HIF-1α causes an increased progression into S phase during hypoxia, rather than a growth arrest. We show that hypoxia causes a HIF-1α-dependent increase in the expression of the cyclin-dependent kinase inhibitors p21 and p27; we also find that hypophosphorylation of retinoblastoma protein in hypoxia is HIF-1α dependent. These data demonstrate that the transcription factor HIF-1 is a major regulator of cell cycle arrest in primary cells during hypoxia.

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 Induction of the HIF pathway: Differential regulation by chemical hypoxia and oxygen glucose deprivation

2019 ◽  
Author(s):  
Alicia E. Novak ◽  
Susan M. Jones ◽  
J. Paul Elliott
Keyword(s):  
Transcriptional Activation ◽  
Cellular Response ◽  
Target Genes ◽  
Expression Patterns ◽  
Hypoxia Inducible Factor ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Oxygen Levels ◽  
Chemical Hypoxia ◽  
Hif Pathway

AbstractThe Hypoxia Inducible Factor (HIF) proteins are the master regulators in the cellular response to varying oxygen levels, including hypoxia. The HIF complex is stabilized and accumulates when oxygen levels drop through inhibition of a degradative enzyme. An active HIF complex can act as a transcriptional regulator of hundreds of genes. In turn, these genes determine the response of the cell by inducing pathways which can promote survival, or result in cell death. However, little is known about the regulation of the transcriptional process. We were interested in learning more about the time dependence of transcriptional activation in order to target those pathways which could enhance cell survival after ischemia. Using mouse hippocampal organotypic cultures (HOTCs), we compared oxygen-glucose deprivation with the hypoxia mimetic cobalt, which inhibits the oxygen dependent prolyl hydroylase and blocks degradation of the HIF proteins. We demonstrated that two of the most studied HIF target genes (VEGF, EPO) as well as HIF structural genes show complex time and dose-dependent expression patterns in response to the two different insults. Understanding of these molecular responses is crucial for the development of future treatments to enhance recovery from hypoxia and stroke.

scholarly journals Integrin α6 upregulation in nucleus pulposus cell under high oxygen tension attenuates intervertebral disc degeneration

2021 ◽  
Author(s):  
Zeng Xu ◽  
Jiancheng Zheng ◽  
Ying Zhang ◽  
Huiqiao Wu ◽  
Bin Sun ◽  
...  
Keyword(s):  
Oxygen Tension ◽  
Protective Factor ◽  
Cell Function ◽  
Hypoxia Inducible Factor ◽  
Nucleus Pulposus Cell ◽  
Intervertebral Disk ◽  
High Oxygen ◽  
Low Oxygen ◽  
Induced Apoptosis

AbstractThe destruction of low oxygen microenvironment played critical roles in the pathogenesis of intervertebral disk degeneration (IVDD). In this study, high oxygen tension (HOT) treatment upregulated integrin α6(ITG α6) expression, which could be alleviated by blocking PI3K/AKT signaling pathway. And the levels of ITG α6 expression were increased in the NP tissue from IVDD patients and IVDD rat model with mild degeneration, which were reduced as degeneration degree increases. Further studies found that ITG α6 could protect NP cells against HOT-induced apoptosis and oxidative stress, and protect NP cells from HOT-inhibited ECM proteins synthesis. ITG α6 upregulation by HOT contributed to maintain a NP tissue homeostasis through the interaction with hypoxia inducible factor-1α (HIF-1α). Furthermore, silencing of ITG α6 in vivo could obviously accelerate puncture-induced IVDD. Taken together, ITG α6 upregulation by HOT in NP cells might be a protective factor in IVDD as well as restore NP cell function.

scholarly journals Inverse Regulation of Early and Late Chondrogenic Differentiation by Oxygen Tension Provides Cues for Stem Cell-Based Cartilage Tissue Engineering

2015 ◽  
Vol 35 (3) ◽  
pp. 841-857 ◽  
Author(s):  
Sophie Portron ◽  
Vincent Hivernaud ◽  
Christophe Merceron ◽  
Julie Lesoeur ◽  
Martial Masson ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Oxygen Tension ◽  
Stromal Cells ◽  
Chondrogenic Differentiation ◽  
Transcriptional Activity ◽  
Hypoxia Inducible Factor ◽  
Cartilage Tissue Engineering ◽  
Cartilage Tissue ◽  
Low Oxygen ◽  
Dna Binding Assay

Background/Aims: Multipotent stem/stromal cells (MSC) are considered promising for cartilage tissue engineering. However, chondrogenic differentiation of MSC can ultimately lead to the formation of hypertrophic chondrocytes responsible for the calcification of cartilage. To prevent the production of this calcified matrix at the articular site, the late hypertrophic differentiation of MSCs must be carefully controlled. Given that articular cartilage is avascular, we hypothesized that in addition to its stimulatory role in the early differentiation of chondrogenic cells, hypoxia may prevent their late hypertrophic conversion. Methods: Early and late chondrogenic differentiation were evaluated using human adipose MSC and murine ATDC5 cells cultured under either normoxic (21%O2) or hypoxic (5%O2) conditions. To investigate the effect of hypoxia on late chondrogenic differentiation, the transcriptional activity of hypoxia-inducible factor-1alpha (HIF-1α) and HIF-2α were evaluated using the NoShift DNA-binding assay and through modulation of their activity (chemical inhibitor, RNA interference). Results: Our data demonstrate that low oxygen tension not only stimulates the early chondrogenic commitment of two complementary models of chondrogenic cells, but also inhibits their hypertrophic differentiation. Conclusion: These results suggest that hypoxia can be used as an instrumental tool to prevent the formation of a calcified matrix in MSC-based cartilage tissue engineering.

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