scholarly journals Structural Characterization of the Interaction of Hypoxia Inducible Factor-1 with Its Hypoxia Responsive Element at the −964G > A Variation Site of the HLA-G Promoter Region

2021 ◽  
Vol 22 (23) ◽  
pp. 13046
Author(s):  
Cinthia C. Alves ◽  
Eduardo A. Donadi ◽  
Silvana Giuliatti
Keyword(s):  
Promoter Region ◽  
Quaternary Structure ◽  
Homology Modelling ◽  
Hypoxia Inducible Factor ◽  
Data Bank ◽  
Regulatory Elements ◽  
Covalent Bonds ◽  
Exon 2 ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxic Conditions

Human Antigen Leukocyte-G (HLA-G) gene encodes an immune checkpoint molecule that has restricted tissue expression in physiological conditions; however, the gene may be induced in hypoxic conditions by the interaction with the hypoxia inducible factor-1 (HIF1). Hypoxia regulatory elements (HRE) located at the HLA-G promoter region and at exon 2 are the major HIF1 target sites. Since the G allele of the −964G > A transversion induces higher HLA-G expression when compared to the A allele in hypoxic conditions, here we analyzed HIF1-HRE complex interaction at the pair-atom level considering both −964G > A polymorphism alleles. Mouse HIF2 dimer crystal (Protein Data Bank ID: 4ZPK) was used as template to perform homology modelling of human HIF1 quaternary structure using MODELLER v9.14. Two 3D DNA structures were built from 5′GCRTG’3 HRE sequence containing the −964G/A alleles using x3DNA. Protein-DNA docking was performed using the HADDOCK v2.4 server, and non-covalent bonds were computed by DNAproDB server. Molecular dynamic simulation was carried out per 200 ns, using Gromacs v.2019. HIF1 binding in the HRE containing −964G allele results in more hydrogen bonds and van der Waals contact formation than HRE with −964A allele. Protein-DNA complex trajectory analysis revealed that HIF1-HRE-964G complex is more stable. In conclusion, HIF1 binds in a more stable and specific manner at the HRE with G allele.

Matriptase-2 (TMPRSS6) is directly up-regulated by hypoxia inducible factor-1: identification of a hypoxia-responsive element in the TMPRSS6 promoter region

2012 ◽  
Vol 393 (6) ◽  
pp. 535-540 ◽  
Author(s):  
Eva Maurer ◽  
Michael Gütschow ◽  
Marit Stirnberg
Keyword(s):  
Promoter Region ◽  
Iron Homeostasis ◽  
Hypoxia Inducible Factor ◽  
Type Ii ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxic Conditions ◽  
Hypoxia Responsive Element ◽  
Responsive Element ◽  
Main Regulator ◽  
Transmembrane Serine Protease

Abstract The type II transmembrane serine protease matriptase-2 (TMPRSS6) down-regulates the expression of hepcidin, the main regulator of systemic iron homeostasis, and increases in this way iron plasma levels. Matriptase-2 is up-regulated under hypoxic conditions, providing a new link between hypoxia signaling and iron homeostasis. In this study, we have characterized the TMPRSS6 promoter region and identified a functional hypoxia-responsive element (HRE). Mutations of the hypoxia inducible factor (HIF)-binding site located within the HRE abrogate HIF-1α-dependent induction of TMPRSS6 expression. The action of HIF-1α on TMPRSS6 promoter activity reveals a new regulative element for the suppression of hepcidin synthesis.

scholarly journals Neuroglobin Regulates Hypoxic Response of Neuronal Cells through Hif-1α- and Nrf2-mediated Mechanism

2012 ◽  
Vol 32 (6) ◽  
pp. 1046-1060 ◽  
Author(s):  
Kalpana B Hota ◽  
Sunil K Hota ◽  
Ravi B Srivastava ◽  
Shashi B Singh
Keyword(s):  
Cytochrome C ◽  
Acute Hypoxia ◽  
Neuronal Cells ◽  
Hypoxia Inducible Factor ◽  
Redox Status ◽  
Related Factor ◽  
Cytochrome C Release ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxic Conditions ◽  
Cellular Antioxidants

Oxygen sensing in hypoxic neurons has been classically attributed to cytochrome c oxidase and prolyl-4-hydroxylases and involves stabilization of transcription factors, hypoxia-inducible factor-1 α (Hif-1 α) and nuclear factor erythroid 2-related factor 2 (Nrf2) that mediate survival responses. On the contrary, release of cytochrome c into the cytosol during hypoxic stress triggers apoptosis in neuronal cells. We, here advocate that the redox state of neuroglobin (Ngb) could regulate both Hif-1 α and Nrf2 stabilization and cytochrome c release during hypoxia. The hippocampal regions showing higher expression of Ngb were less susceptible to global hypoxia-mediated neurodegeneration. During normoxia, Ngb maintained cytochrome c in the reduced state and prevented its release from mitochondria by using cellular antioxidants. Greater turnover of oxidized cytochrome c and increased utilization of cellular antioxidants during acute hypoxia altered cellular redox status and stabilized Hif-1 α and Nrf2 through Ngb-mediated mechanism. Chronic hypoxia, however, resulted in oxidation and degradation of Ngb, accumulation of ferric ions and release of cytochrome c that triggered apoptosis. Administration of N-acetyl-cysteine during hypoxic conditions improved neuronal survival by preventing Ngb oxidation and degradation. Taken together, these results establish a role for Ngb in regulating both the survival and apoptotic mechanisms associated with hypoxia.

scholarly journals Hypoxia Rapidly Induces the Expression of Cardiomyogenic Factors in Human Adipose-Derived Adherent Stromal Cells

2019 ◽  
Vol 8 (8) ◽  
pp. 1231
Author(s):  
Choi ◽  
Moon ◽  
Jung ◽  
Lim ◽  
Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stromal Cells ◽  
Hypoxia Inducible Factor ◽  
In Vivo Studies ◽  
Hypoxic Stress ◽  
Differentiation Markers ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxic Conditions ◽  
Fibroblast Growth Factor 19

Background: The efficacy of interstitial vascular fraction (SVF) transplantation in the treatment of heart disease has been proven in a variety of in vivo studies. In a previous study, we found that bone marrow-derived mesenchymal stem cells (BM-MSCs) altered their expression of several cardiomyogenic factors under hypoxic conditions. Methods: We hypothesized that hypoxia may also induce obtained adipose-derived adherent stromal cells (ADASs) from SVFs and adipose-derived stem cells (ASCs) to differentiate into cardiomyocytes and/or cells with comparable phenotypes. We examined the differentiation markers of cell lineages in ADASs and ASCs according to time by hypoxic stress and found that only ADASs expressed cardiomyogenic markers within 24 hours under hypoxic conditions in association with the expression of hypoxia-inducible factor 1-α (HIF-1α). Results: Differentially secreted proteins in a conditioned medium (CM) from ASCs and ADASs under normoxic or hypoxic conditions were detected using an antibody assay and may be associated with a dramatic increase in the expression of cardiomyogenic markers in only ADASs. Furthermore, the cardiomyogenic factors were expressed more rapidly in ADASs than in ASCs under hypoxic conditions in association with the expression of HIF-1α, and angiogenin, fibroblast growth factor-19 (FGF-19) and/or macrophage inhibitory factor (MIF) are related. Conclusions: These results provide new insights into the applicability of ADASs preconditioned by hypoxic stress in cardiac diseases.

scholarly journals Differential roles of prostaglandin E-type receptors in activation of hypoxia-inducible factor 1 by prostaglandin E1in vascular-derived cells under non-hypoxic conditions

PeerJ ◽  
2013 ◽  
Vol 1 ◽  
pp. e220 ◽  
Author(s):  
Kengo Suzuki ◽  
Kenichiro Nishi ◽  
Satoshi Takabuchi ◽  
Shinichi Kai ◽  
Tomonori Matsuyama ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Prostaglandin E ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxic Conditions

scholarly journals HIF-1: the knowns and unknowns of hypoxia sensing.

2004 ◽  
Vol 51 (3) ◽  
pp. 563-585 ◽  
Author(s):  
Anna Zagórska ◽  
Józef Dulak
Keyword(s):  
Transcriptional Activity ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxic Conditions ◽  
Oxygen Homeostasis ◽  
Wide Range ◽  
Systemic Oxygen ◽  
Prolyl Hydroxylation ◽  
Energy Deprivation ◽  
Direct Inhibitors

Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator that functions as a master regulator of cellular and systemic oxygen homeostasis. It consists of two constitutively produced subunits: HIF-1alpha and HIF-1beta. Under normoxic conditions HIF-1alpha undergoes hydroxylation at specific prolyl residues which leads to an immediate ubiquitination and subsequent proteasomal degradation of the alpha subunit. Additionally, hydroxylation of an asparaginyl residue blocks the transcriptional activity of HIF-1 due to inhibition of its interaction with co-activators. In contrast, under hypoxic conditions, abolition of prolyl hydroxylation results in HIF-1alpha stabilization, whereas the lack of asparaginyl hydroxylation allows the transcriptional activity. Additionally, the transcriptional activity may be modulated by phosphorylation or redox modification of HIF-1. Despite its name, HIF-1 is induced not only in response to reduced oxygen availability but also by other stimulants, such as nitric oxide, various growth factors, or direct inhibitors of prolyl and asparaginyl hydroxylases. Therefore, it seems to be a crucial transcription factor elicited by a wide range of stresses such as impaired oxygenation, inflammation, energy deprivation, or intensive proliferation. However, the mechanisms of normoxic activation, as well as of oxygen sensing, are not yet fully known. Further understanding of the processes that control HIF-1 activity will be crucial for the development of new diagnostic and therapeutic strategies.

A new HIF-1 alpha variant induced by zinc ion suppresses HIF-1-mediated hypoxic responses

2001 ◽  
Vol 114 (22) ◽  
pp. 4051-4061
Author(s):  
Yang-Sook Chun ◽  
Eunjoo Choi ◽  
Eun-Jin Yeo ◽  
Jong Ho Lee ◽  
Myung-Suk Kim ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Consensus Sequence ◽  
Hypoxia Inducible Factor ◽  
Zinc Ion ◽  
Dominant Negative ◽  
Hypoxia Inducible Factor 1 ◽  
Aryl Hydrocarbon ◽  
Hypoxic Conditions ◽  
Alpha Variant ◽  
Inducible Genes

The expressions of hypoxia-inducible genes are upregulated by hypoxia-inducible factor 1 (HIF-1), which is a heterodimer of HIF-1α and HIF-1β/ARNT (aryl hydrocarbon receptor nuclear transporter). Under hypoxic conditions, HIF-1α becomes stabilized and both HIF-1α and ARNT are translocated into the nucleus and codimerized, binding to the HIF-1 consensus sequence and transactivating hypoxia-inducible genes. Other than hypoxia, cobalt and nickel, which can substitute for iron in the ferroprotein, induce the stabilization of HIF-1α and the activation of HIF-1. We found previously that, although zinc, another example of a metal substitute for iron, stabilized HIF-1α, it suppressed the formation of HIF-1 by blocking the nuclear translocation of ARNT. Here, we identify a new spliced variant of human HIF-1α that is induced by zinc. The isoform lacks the 12th exon, which produced a frame-shift and gave a shorter form of HIF-1α (557 amino acids), designated HIF-1αZ (HIF-1α induced by Zn). This moiety was found to inhibit HIF-1 activity and reduce mRNA expressions of the hypoxia-inducible genes. It blocked the nuclear translocation of ARNT but not that of endogenous HIF-1α, and was associated with ARNT in the cytosol. These results suggest that HIF-1αZ functions as a dominant-negative isoform of HIF-1 by sequestering ARNT in the cytosol. In addition, the generation of HIF-1αZ seems to be responsible for the inhibitory effects of the zinc ion on HIF-1-mediated hypoxic responses, because the expressed HIF-1αZ behaved in the same manner as zinc in terms of inhibited HIF-1 activity and ARNT translocation.

scholarly journals MiR-194-5p enhances the sensitivity of nonsmall-cell lung cancer to doxorubicin through targeted inhibition of hypoxia-inducible factor-1

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Mengning Xia ◽  
Lili Sheng ◽  
Wei Qu ◽  
Xue Xue ◽  
Hucheng Chen ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Nonsmall Cell Lung Cancer ◽  
Nsclc Cell ◽  
Tunel Staining ◽  
Drug Resistant ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxic Conditions ◽  
Downstream Effectors ◽  
Targeted Inhibition ◽  
Resistance To Doxorubicin

Abstract Background Despite chemotherapy being a common treatment, an increase in chemoresistance over time is unavoidable. We therefore investigated the role of miR-194-5p in regulating chordoma cell behavior and examined the downstream effectors of miR-194-5p. Methods In this study, NSCLC cell lines A549 and H460 were cultured under hypoxic conditions for 1 week to induce drug resistance to doxorubicin (DOX). The connection between miR-194-5p and HIF-1 was revealed by reverse transcription and real-time polymerase chain reaction (RT-qPCR), western blot, and dual-luciferase assays. We used TUNEL staining and the CCK-8 test to assess the sensitivity of NSCLC cells to DOX. Results We found that hypoxia-induced NSCLC cells enhanced resistance to DOX. MiR-194-5p was substantially reduced, and HIF-1 was increased in hypoxia-induced drug-resistant NSCLC cells. Moreover, miR-194-5p successfully induced NSCLC cell apoptosis by directly inhibiting HIF-1, thereby enhancing DOX sensitivity. Conclusions MiR-194-5p enhanced the sensitivity of NSCLC cells to DOX by directly inhibiting HIF-1. This work provides insights into underlying treatments for drug-resistant NSCLC.

scholarly journals Pseudomonas aeruginosa Alkyl Quinolones Repress Hypoxia-Inducible Factor 1 (HIF-1) Signaling through HIF-1α Degradation

2012 ◽  
Vol 80 (11) ◽  
pp. 3985-3992 ◽  
Author(s):  
Claire Legendre ◽  
F. Jerry Reen ◽  
Marlies J. Mooij ◽  
Gerard P. McGlacken ◽  
Claire Adams ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Hypoxia Inducible Factor ◽  
26S Proteasome ◽  
Hexokinase Ii ◽  
Content Type ◽  
Protein Levels ◽  
Hypoxia Inducible Factor 1 ◽  
Hypoxic Conditions ◽  
Secreted Factors ◽  
Proteolytic Pathway

ABSTRACTThe transcription factor hypoxia-inducible factor 1 (HIF-1) has recently emerged to be a crucial regulator of the immune response following pathogen perception, including the response to the important human pathogenPseudomonas aeruginosa. However, as mechanisms involved in HIF-1 activation by bacterial pathogens are not fully characterized, understanding how bacteria and bacterial compounds impact on HIF-1α stabilization remains a major challenge. In this context, we have focused on the effect of secreted factors ofP. aeruginosaon HIF-1 regulation. Surprisingly, we found thatP. aeruginosacell-free supernatant significantly repressed HIF-1α protein levels. Further characterization revealed that HIF-1α downregulation was dependent on a subset of key secreted factors involved inP. aeruginosapathogenesis, the 2-alkyl-4-quinolone (AQ) quorum sensing (QS) signaling molecules, and in particular the pseudomonas quinolone signal (PQS). Under hypoxic conditions, the AQ-dependent downregulation of HIF-1α was linked to the suppressed induction of the important HIF-1 target gene hexokinase II. Furthermore, we demonstrated that AQ molecules directly target HIF-1α protein degradation through the 26S-proteasome proteolytic pathway but independently of the prolyl hydroxylase domain (PHD). In conclusion, this is the first report showing that bacterial molecules can repress HIF-1α protein levels. Manipulation of HIF-1 signaling byP. aeruginosaAQs could have major consequences for the host response to infection and may facilitate the infective properties of this pathogen.

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