scholarly journals Properties of Switch-like Bioregulatory Networks Studied by Simulation of the Hypoxia Response Control System

2004 ◽  
Vol 15 (7) ◽  
pp. 3042-3052 ◽  
Author(s):  
Kurt W. Kohn ◽  
Joseph Riss ◽  
Olga Aprelikova ◽  
John N. Weinstein ◽  
Yves Pommier ◽  
...  
Keyword(s):  
Cellular Response ◽  
Synthesis Rate ◽  
Growth Factor Signaling ◽  
Simulation Studies ◽  
Response Control ◽  
Hypoxia Response ◽  
Von Hippel Lindau ◽  
Response Characteristics ◽  
Interaction Map ◽  
Conserved Core

A complex bioregulatory network could be more easily comprehended if its essential function could be described by a small “core” subsystem, and if its response characteristics were switch-like. We tested this proposition by simulation studies of the hypoxia response control network. We hypothesized that a small subsystem governs the basics of the cellular response to hypoxia and that this response has a sharp oxygen-dependent transition. A molecular interaction map of the network was prepared, and an evolutionarily conserved core subsystem was extracted that could control the activity of hypoxia response promoter elements on the basis of oxygen concentration. The core subsystem included the hypoxia-inducible transcription factor (HIFα:ARNT heterodimer), proline hydroxylase, and the von Hippel-Lindau protein. Simulation studies showed that the same core subsystem can exhibit switch-like responses both to oxygen level and to HIFα synthesis rate, thus suggesting a mechanism for hypoxia response promoter element-dependent responses common to both hypoxia and growth factor signaling. The studies disclosed the mechanism responsible for the sharp transitions. We show how parameter sets giving switch-like behavior can be found and how this type of behavior provides a foundation for quantitative studies in cells.

scholarly journals RNA-seq analysis of PHD and VHL inhibitors reveals differences and similarities to the hypoxia response.

2019 ◽  
Vol 4 ◽  
pp. 17 ◽  
Author(s):  
Julianty Frost ◽  
Alessio Ciulli ◽  
Sonia Rocha
Keyword(s):  
Cellular Response ◽  
Hypoxia Inducible Factor ◽  
Gene Activation ◽  
Transcriptional Response ◽  
Dependent Manner ◽  
Rna Seq ◽  
Pharmacological Agents ◽  
Hypoxia Response ◽  
Von Hippel Lindau ◽  
Large Numbers

Background:Hypoxia-inducible factor (HIF) transcription factors are well known to control the transcriptional response to hypoxia. Given the importance of cellular response to hypoxia, a number of pharmacological agents to interfere with this pathway have been developed and entered pre-clinical or clinical trial phases. However, how similar or divergent the transcriptional response elicited by different points of interference in cells is currently unknown.Methods:We performed RNA-sequencing to analyse the similarities and differences of transcriptional response in HeLa cells treated with hypoxia or chemical agents that stabilise HIF by inhibiting components of the hypoxia signalling pathway – prolyl hydroxylase (PHD) inhibitor or von Hippel–Lindau (VHL) inhibitor.Results:This analysis revealed that hypoxia produces the highest changes in gene transcription, with activation and repression of genes being in large numbers. Treatment with the PHD inhibitor IOX2 or the VHL inhibitor VH032 led mostly to gene activation, majorly via a HIF-dependent manner. These results were also confirmed by qRT-PCR using more specific and/or efficient inhibitors, FG-4592 (PHDs) and VH298 (VHL).Conclusion:PHD inhibition and VHL inhibition mimic gene activation promoted by hypoxia via a HIF-dependent manner. However, gene repression is mostly associated with the hypoxia response and not common to the response elicited by inhibitors of the pathway.

scholarly journals Zebrafish Hif3α modulates erythropoiesis via regulation of gata1 to facilitate hypoxia tolerance

Development ◽  
2020 ◽  
Vol 147 (22) ◽  
pp. dev185116
Author(s):  
Xiaolian Cai ◽  
Ziwen Zhou ◽  
Junji Zhu ◽  
Qian Liao ◽  
Dawei Zhang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cellular Response ◽  
Transcriptional Activity ◽  
Hypoxia Tolerance ◽  
Cell Maturation ◽  
Marker Genes ◽  
Hypoxia Inducible Factors ◽  
Hypoxia Response Element ◽  
Hypoxia Response ◽  
Master Regulators

ABSTRACTThe hypoxia-inducible factors 1α and 2α (HIF1α and HIF2α) are master regulators of the cellular response to O2. In addition to HIF1α and HIF2α, HIF3α is another identified member of the HIFα family. Even though the question of whether some HIF3α isoforms have transcriptional activity or repressive activity is still under debate, it is evident that the full length of HIF3α acts as a transcription factor. However, its function in hypoxia signaling is largely unknown. Here, we show that loss of hif3a in zebrafish reduced hypoxia tolerance. Further assays indicated that erythrocyte number was decreased because red blood cell maturation was impeded by hif3a disruption. We found that gata1 expression was downregulated in hif3a null zebrafish, as were several hematopoietic marker genes, including alas2, band3, hbae1, hbae3 and hbbe1. Hif3α recognized the hypoxia response element located in the promoter of gata1 and directly bound to the promoter to transactivate gata1 expression. Our results suggested that hif3a facilities hypoxia tolerance by modulating erythropoiesis via gata1 regulation.

scholarly journals Activation of the Hypoxia-Inducible Factor Pathway Expands Early Thymic Progenitors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2896-2896
Author(s):  
Anita Hollenbeck ◽  
Stefanie Weber ◽  
Kathrin Händschke ◽  
Mandy Necke ◽  
Bertram Opalka ◽  
...  
Keyword(s):  
Cellular Response ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Cell Receptor ◽  
Normal Numbers ◽  
Cellular Compartment ◽  
Vhl Gene ◽  
Von Hippel Lindau

Abstract Early thymic progenitors enter the thymus and are exposed to regional hypoxia while they develop in a step-wise manner to mature functional T-cells. Therefore, hypoxia might represent an important component of the highly specialized thymic microenvironment. On the molecular level the hypoxia-inducible factor pathway controls the cellular response to hypoxia. In this pathway, the von-Hippel-Lindau protein (pVHL) continuously mediates the destruction of the transcription factor hypoxia-inducible factor-1α (HIF-1α) under normoxic conditions. Under hypoxia HIF-1α degradation is inhibited leading to the activation of HIF-1α target genes. Others used lck-Cre transgene-mediated conditional in vivo deletion of the Vhl gene to study the role of the oxygen-sensing pathway in developing thymocytes and found normal numbers of early double-negative (DN; CD4-CD8-) thymocytes (Biju et al., Mol Cell Biol, 2004). However, lck-Cre deletion initiates at the DN3 (CD25+CD44-) stage leaving the Vhl locus of very early DN1 (CD25-CD44+), DN2 (CD25+CD44+) and DN3 thymocytes unaltered. Therefore, we here used the ubiquitous hematopoietic deleter strain vav-Cre to investigate the role of pVHL in very early thymocytes (vav-Cre;VhlloxP;loxP mice). Using a PCR-based strategy we confirmed complete deletion of the Vhl gene in this model. We observed unaltered DN1 and DN2 progenitor numbers, however in contrast to the published lck-cre-mediated system we consistently observed an up to twofold expansion of the DN3 cellular compartment. As the hypoxia-inducible factor pathway was shown to modulate NOTCH1 signaling we studied Notch1 expression on Vhl-deficient thymocytes. Strikingly, Notch1 expression was significantly increased on expanded Vhl null DN3 thymocytes. At the DN3 developmental stage selection of cells with an accurately re-arranged T-cell receptor β-locus occurs. Thus, we analyzed pre- and post-β-selection DN3 cells by CD28 staining. Interestingly, we found both pre- and post-β-selection DN3 subpopulations expanded. In order to investigate whether the progenitor expansion is mediated by the lack of HIF-1α inhibition in the Vhl-deficient context we studied DN3 thymocytes in a conditional hematopoietic HIF-1α gain-of-function model (vav-Cre;HIF1dPA). Overexpression of HIF-1α, which is insensitive to pVHL-mediated degradation in vav-Cre;HIF1dPAmice, also resulted in expanded DN3 thymocytes. In summary, we describe novel conditional models to genetically alter the hypoxia-inducible factor pathway within very early thymic progenitors. Genetic Vhl loss led to an expansion of DN3 thymocytes. This DN3 expansion is most likely due to the absence of HIF-1α-inhibition, because HIF-1α overexpression phenocopied the Vhl-deficient DN3 thymocyte expansion. Disclosures Dührsen: Celgene: Honoraria, Research Funding.

The von Hippel-Lindau gene mutation is associated with the good-prognosis profiling subtype of clear cell renal cell carcinoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4532-4532
Author(s):  
M. Tan ◽  
B. Teh
Keyword(s):  
Gene Expression ◽  
Expression Profiling ◽  
Clear Cell ◽  
Univariate Analysis ◽  
Good Prognosis ◽  
Effect Modification ◽  
Cell Renal Cell Carcinoma ◽  
Hypoxia Response ◽  
Vhl Gene ◽  
Von Hippel Lindau

4532 Background: The prevalence of von Hippel-Lindau (VHL) mutations in clear cell renal cell carcinoma (ccRCC) is about 30–50%. The association between VHL mutation and patient prognosis remains controversial, despite extensive in vitro research on its role in hypoxia response. We have previously reported a robust prognostic classification of ccRCC using gene expression profiling. In view of reports of activity of anti-angiogenesis agents, we studied the association of VHL mutation with tumor profiling subtypes, survival and other clinical parameters. Methods: All exons of the VHL gene in 88 ccRCC samples were sequenced. Expression profiling using oligonucleotide arrays (54,675 probe sets) was also performed, and the samples classified using hierarchical clustering. For identification of VHL mutation specific signatures, nearest shrunken centroids with internal validation was used with a 10% misclassification cutoff. Results: 35% of the samples had VHL mutations. Mutation status was not significantly associated with survival on univariate analysis (p = 0.54). Hierarchical clustering yielded two ccRCC subtypes with divergent clinical outcomes (HR = 4.13, p < 0.001). VHL mutations were significantly associated with the good-prognosis profiling subtype of ccRCC tumors (OR 3.3, p = 0.04), but no effect modification between VHL mutation and the prognostic subtypes was found (p=0.31). No standard clinical parameter was associated with VHL mutation. No significant association between VHL mutation and downstream hypoxia response gene expression, including VEGF (p = 0.14), PDGF (p = 0.5), TGF-A (p = 0.24) and GLUT1 (p = 0.45) was found. Conclusion: While VHL mutation is associated with a biologically distinct good-prognosis profiling tumor subtype, its lack of prognostic value on univariate analysis suggests an expanded study to evaluate effect modification. The absence of a specific gene classifier for VHL mutation and the lack of association between VHL gene mutation and known hypoxia response genes suggest that VHL mutations result in heterogenous tissue phenotypes. These results support molecular subtyping of ccRCC in laboratory and clinical studies; in particular, this may be critical for trials involving anti-angiogenesis agents. No significant financial relationships to disclose.

scholarly journals Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization

2017 ◽  
Vol 114 (37) ◽  
pp. 9948-9953 ◽  
Author(s):  
Andrea Vettori ◽  
David Greenald ◽  
Garrick K. Wilson ◽  
Margherita Peron ◽  
Nicola Facchinello ◽  
...  
Keyword(s):  
Cross Talk ◽  
Cellular Response ◽  
Isolated Hepatocytes ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Transcriptional Responses ◽  
Human Liver Tissue ◽  
Von Hippel Lindau ◽  
Response To Stress

Glucocorticoid (GC) and hypoxic transcriptional responses play a central role in tissue homeostasis and regulate the cellular response to stress and inflammation, highlighting the potential for cross-talk between these two signaling pathways. We present results from an unbiased in vivo chemical screen in zebrafish that identifies GCs as activators of hypoxia-inducible factors (HIFs) in the liver. GCs activated consensus hypoxia response element (HRE) reporters in a glucocorticoid receptor (GR)-dependent manner. Importantly, GCs activated HIF transcriptional responses in a zebrafish mutant line harboring a point mutation in the GR DNA-binding domain, suggesting a nontranscriptional route for GR to activate HIF signaling. We noted that GCs increase the transcription of several key regulators of glucose metabolism that contain HREs, suggesting a role for GC/HIF cross-talk in regulating glucose homeostasis. Importantly, we show that GCs stabilize HIF protein in intact human liver tissue and isolated hepatocytes. We find that GCs limit the expression of Von Hippel Lindau protein (pVHL), a negative regulator of HIF, and that treatment with the c-src inhibitor PP2 rescued this effect, suggesting a role for GCs in promoting c-src–mediated proteosomal degradation of pVHL. Our data support a model for GCs to stabilize HIF through activation of c-src and subsequent destabilization of pVHL.

scholarly journals Lipid rafts in glial cells: role in neuroinflammation and pain processing

2019 ◽  
Vol 61 (5) ◽  
pp. 655-666 ◽  
Author(s):  
Yury I. Miller ◽  
Juliana M. Navia-Pelaez ◽  
Maripat Corr ◽  
Tony L. Yaksh
Keyword(s):  
Ion Channels ◽  
Lipid Rafts ◽  
Glial Cells ◽  
Cellular Response ◽  
Protein Complexes ◽  
Large Population ◽  
Inflammatory Cells ◽  
Sphingolipid Metabolism ◽  
Response Characteristics ◽  
Pain State

Activation of microglia and astrocytes secondary to inflammatory processes contributes to the development and perpetuation of pain with a neuropathic phenotype. This pain state presents as a chronic debilitating condition and affects a large population of patients with conditions like rheumatoid arthritis and diabetes, or after surgery, trauma, or chemotherapy. Here, we review the regulation of lipid rafts in glial cells and the role they play as a key component of neuroinflammatory sensitization of central pain signaling pathways. In this context, we introduce the concept of an inflammaraft (i-raft), enlarged lipid rafts harboring activated receptors and adaptor molecules and serving as an organizing platform to initiate inflammatory signaling and the cellular response. Characteristics of the inflammaraft include increased relative abundance of lipid rafts in inflammatory cells, increased content of cholesterol per raft, and increased levels of inflammatory receptors, such as toll-like receptor (TLR)4, adaptor molecules, ion channels, and enzymes in lipid rafts. This inflammaraft motif serves an important role in the membrane assembly of protein complexes, for example, TLR4 dimerization. Operating within this framework, we demonstrate the involvement of inflammatory receptors, redox molecules, and ion channels in the inflammaraft formation and the regulation of cholesterol and sphingolipid metabolism in the inflammaraft maintenance and disruption. Strategies for targeting inflammarafts, without affecting the integrity of lipid rafts in noninflammatory cells, may lead to developing novel therapies for neuropathic pain states and other neuroinflammatory conditions.

scholarly journals Dimensionless quantification of small radial turbine transient performance

2020 ◽  
Vol 235 (1) ◽  
pp. 188-198
Author(s):  
Qiyou Deng ◽  
Andrew Pennycott ◽  
Qingning Zhang ◽  
Calogero Avola ◽  
Ludek Pohorelsky ◽  
...  
Keyword(s):  
Dynamic Behaviour ◽  
Internal Flow ◽  
Simulation Studies ◽  
Dimensionless Parameters ◽  
Transient Behaviour ◽  
Response Characteristics ◽  
Radial Turbine ◽  
Housing Temperature ◽  
Turbine Housing ◽  
Modelling Approach

Turbochargers are inherently dynamic devices, comprising internal flow volumes, mechanical inertias and thermal masses. When operating under transient conditions within an engine system, these dynamics need to be better understood. In this paper, a new non-dimensional modelling approach to characterise the turbocharger is proposed. Two new dimensionless quantities are defined with respect to mechanical and thermal transient behaviour, which are used in conjunction with the Strouhal number for flow transients. The modelling approach is applied to a small wastegated turbocharger and validated against experimental results. The model is used to simulate the turbocharger mass flow rate, turbine housing temperature and shaft speed responses to different excitation frequencies for different sizes of turbine. The results highlight the influence of turbocharger size on the dynamic behaviour of the system, which is particularly marked for the turbine housing temperature. At certain frequency ranges, the system behaviour is quasi-steady, allowing modelling through static maps in these operating regions. Outside these ranges, however, transient elements play a more important role. The simulation study shows that the proposed dimensionless parameters can be used to normalise the influence of turbine size on the dynamic response characteristics of the system. The model and corresponding dimensionless parameters can be applied in future simulation studies as well as for turbocharger matching in industry.

scholarly journals Coordinated Sending-End Power System Frequency Regulation via UHVDC

Electronics ◽  
2021 ◽  
Vol 10 (16) ◽  
pp. 1909
Author(s):  
Qiaoming Shi ◽  
Hongqing Liu ◽  
Kai Liu ◽  
Yongping Wang ◽  
Qingwu Zhang ◽  
...  
Keyword(s):  
Frequency Response ◽  
Operating Conditions ◽  
Frequency Deviation ◽  
Frequency Regulation ◽  
Control Parameters ◽  
Response Control ◽  
Response Characteristics ◽  
Frequency Response Characteristics ◽  
System Frequency ◽  
Inertia Response

The continuous improvement of new energy penetration reduces the inertia of the system, which leads to the frequency deviation and the rate of change of frequency (RoCoF) being easily exceeded. To improve the frequency stability of sending-end power systems with large-scale renewable energy access via ultra-high voltage direct current (UHVDC), the coordinated frequency control for UHVDC participating in system frequency regulation (FR) including primary FR and system inertial response is presented. Based on the simplified system model, the mechanism of UHVDC participation in system frequency support and its influence on receiving-end system frequency response characteristics are analyzed. Compared with the inertia response and primary FR of traditional synchronous generators, the parameter calculating method of UHVDC coordinated frequency response control is proposed. Based on the system root trajectory analysis, the influence of the frequency response control parameters on the sending-end system’s stability is analyzed, and the constraints of UHVDC participating in the system frequency response control are analyzed. Then, based on the RTDS verification platform containing the Lingshao ±800 kV UHVDC control and protection system, the system frequency response characteristics under different control strategies, operating conditions and control parameters are verified and analyzed. The experimental results show that the UHVDC frequency coordinated control can effectively increase the equivalent inertia of the sending-end system, restrain the RoCoF and the frequency deviation, and increase the FR capability of the UHVDC system.

Hypoxia-inducible factor prolyl 4-hydroxylases: common and specific roles

2013 ◽  
Vol 394 (4) ◽  
pp. 435-448 ◽  
Author(s):  
Johanna Myllyharju ◽  
Peppi Koivunen
Keyword(s):  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Drug Candidate ◽  
Hypoxia Response ◽  
Von Hippel Lindau ◽  
Ubiquitin Ligase Complex ◽  
Biological Studies ◽  
The Common

Abstract Hypoxia-inducible transcription factor (HIF), an αβ dimer, is the key inducer of hypoxia-responsive genes that operate both during normal development and pathological processes in association with decreased oxygen availability. The products of HIF target genes function in, e.g., hematopoiesis, angiogenesis, iron transport, glucose utilization, resistance to oxidative stress, cell proliferation, survival and apoptosis, extracellular matrix homeostasis, and tumorigenesis and metastasis. HIF is accumulated in hypoxia, whereas it is rapidly degraded in normoxic cells. The oxygen-sensing mechanism behind this phenomenon is provided by HIF prolyl 4-hydroxylases (HIF-P4Hs, commonly known as PHDs and EglNs) that require oxygen in their reaction. In normoxia, two prolines in the oxygen-dependent degradation domain of the HIFα subunit become hydroxylated by the HIF-P4Hs. The 4-hydroxyproline residues formed serve as recognition sites for the von Hippel-Lindau E3 ubiquitin ligase complex and result in subsequent ubiquitination and instant proteasomal degradation of HIFα in normoxia. The HIF-P4H reaction is inhibited in hypoxia. HIFα evades degradation and forms a functional dimer with HIFβ, leading to activation of the HIF target genes. The central role of HIF-P4Hs in the regulation of the hypoxia response pathway has provided an attractive possibility as a drug candidate for treatment of, e.g., severe anemias and ischemic conditions, and several companies are currently carrying out clinical studies on the use of HIF-P4H inhibitors to treat anemia in patients with a kidney disease. Therefore, it is important to understand the effects of individual HIF-P4H isoenzymes on the hypoxia response and potential other pathways in vivo. The common and specific functions of the HIF-P4H isoenzymes are discussed in this review on the basis of available data from cell biological studies and gene-modified animals.

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