Epolones induce erythropoietin expression via hypoxia-inducible factor-1α activation

Wanner, Roger M.; Spielmann, Patrick; Stroka, Deborah; Camenisch, Gieri; Camenisch, Isabelle; Scheid, Annette; Houck, David R.; Bauer, Christian; Gassmann, Max; Wenger, Roland H.

doi:10.1182/blood.v96.4.1558.h8001558_1558_1565

Cited by 28 publications

(21 citation statements)

References 40 publications

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“…Needless to say, we cannot rigorously rule out the possibility that factors other than Epo, which are specifically regulated by HLF, are involved in proliferative vascularization. Despite its normal expression in HLF kd/kd mice, HIF‐1α cannot functionally compensate for HLF in this process, while Epo gene expression is known to be regulated by both HIF‐1α and HLF through the HRE located downstream of the gene by DNA transfection assays (Wanner et al ., 2000). It remains to be elucidated why only HLF, but not HIF‐1α, transactivates the expression of the Epo gene in the retinas of ROP.…”

Section: Discussionmentioning

confidence: 99%

HLF/HIF-2α is a key factor in retinopathy of prematurity in association with erythropoietin

Morita

Onodera

Yamashita

et al. 2003

EMBO J

219

154

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M.Morita and O.Ohneda contributed equally to this workAn HLF (HIF-1a-like factor)/HIF-2a-knockout mouse is embryonic lethal, preventing investigation of HLF function in adult mice. To investigate the role of HLF in adult pathological angiogenesis, we generated HLF-knockdown (HLF kd/kd ) mice by inserting a neomycin gene sandwiched between two loxP sequences into exon 1 of the HLF gene. HLF kd/kd mice expressing 80±20% reduction, depending on the tissue, in wildtype HLF mRNA were fertile and apparently normal. Hyperoxia±normoxia treatment, used as a murine model of retinopathy of prematurity (ROP), induced neovascularization in wild-type mice, but not in HLF kd/kd mice, whereas prolonged normoxia following hyperoxic treatment caused degeneration of retinal neural layers in HLF kd/kd mice due to poor vascularization. Cre-mediated removal of the inserted gene recovered normal HLF expression and retinal neovascularization in HLF kd/kd mice. Expression levels of various angiogenic factors revealed that only erythropoietin (Epo) gene expression was signi®cantly affected, in parallel with HLF expression. Together with the results from intraperitoneal injection of Epo into HLF kd/kd mouse, this suggests that Epo is one of the target genes of HLF responsible for experimental ROP.

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Section: Discussionmentioning

confidence: 99%

HLF/HIF-2α is a key factor in retinopathy of prematurity in association with erythropoietin

Morita

Onodera

Yamashita

et al. 2003

EMBO J

219

154

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“…All constructs were verified by sequencing (Microsynth). pH3SVL ( 16 ), PHD2 ( 17 ), PAI-1 and CAIX ( 18 ) reporter gene constructs were described previously.…”

Section: Methodsmentioning

confidence: 99%

Destruction of a distal hypoxia response element abolishestrans-activation of thePAG1gene mediated by HIF-independent chromatin looping

et al. 2015

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A crucial step in the cellular adaptation to oxygen deficiency is the binding of hypoxia-inducible factors (HIFs) to hypoxia response elements (HREs) of oxygen-regulated genes. Genome-wide HIF-1α/2α/β DNA-binding studies revealed that the majority of HREs reside distant to the promoter regions, but the function of these distal HREs has only been marginally studied in the genomic context. We used chromatin immunoprecipitation (ChIP), gene editing (TALEN) and chromosome conformation capture (3C) to localize and functionally characterize a 82 kb upstream HRE that solely drives oxygen-regulated expression of the newly identified HIF target gene PAG1. PAG1, a transmembrane adaptor protein involved in Src signalling, was hypoxically induced in various cell lines and mouse tissues. ChIP and reporter gene assays demonstrated that the −82 kb HRE regulates PAG1, but not an equally distant gene further upstream, by direct interaction with HIF. Ablation of the consensus HRE motif abolished the hypoxic induction of PAG1 but not general oxygen signalling. 3C assays revealed that the −82 kb HRE physically associates with the PAG1 promoter region, independent of HIF-DNA interaction. These results demonstrate a constitutive interaction between the −82 kb HRE and the PAG1 promoter, suggesting a physiologically important rapid response to hypoxia.

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“…Cells were allowed to grow on 24-well plates before they were transiently transfected with a hypoxia-responsive luciferase plasmid which contains six HIF-1 binding sites from the transferrin 3′ enhancer. 37 Empty control vector (pGL4 vector, Promega, Mannheim, Germany) served as transfection control. Medium was renewed 24 hrs after transient transfection.…”

Section: Luciferase Reporter Gene Assaymentioning

confidence: 99%

<p>The Nuclear Export Inhibitor Selinexor Inhibits Hypoxia Signaling Pathways And 3D Spheroid Growth Of Cancer Cells</p>

Depping

Fallois

Landesman

et al. 2019

OTT

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Purpose: The nucleocytoplasmic transport of macromolecules is critical for both cell physiology and pathophysiology. Exportin 1 (XPO1), the major nuclear export receptor, is involved in the cellular adaptation to reduced oxygen availability by controlling the nuclear activity of the hypoxia-inducible factors (HIFs). Recently, a specific inhibitor of XPO1, selinexor (KPT-330), has been identified that inhibits nuclear export of cargo proteins by binding to the XPO1 cargo-binding pocket. Patients and methods: We used different cancer cell lines from human tissues and evaluated the physiological activity of selinexor on the hypoxia response pathway in twodimensional (2D) monolayer cell cultures in quantitative real-time (qRT)-PCR experiments and luciferase reporter gene assays. A three-dimensional (3D) tumor spheroid culture model of MCF-7 breast cancer cells was established to analyze the effect of selinexor on 3D tumor spheroid structure, formation and viability. Results: Selinexor treatment reduces HIF-transcriptional activity and expression of the HIF-1 target gene solute carrier family 2 member 1 (SLC2A1). Moreover, 3D tumor spheroid structure, formation and viability are inhibited in response to selinexor-induced nuclear export inhibition. Conclusion: Here, we demonstrate the effect of specific XPO1-inhibition on the hypoxic response on the molecular level in 2D and 3D culture models of MCF-7 cells.

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Epolones induce erythropoietin expression via hypoxia-inducible factor-1α activation

Cited by 28 publications

References 40 publications

HLF/HIF-2α is a key factor in retinopathy of prematurity in association with erythropoietin

HLF/HIF-2α is a key factor in retinopathy of prematurity in association with erythropoietin

Destruction of a distal hypoxia response element abolishestrans-activation of thePAG1gene mediated by HIF-independent chromatin looping

<p>The Nuclear Export Inhibitor Selinexor Inhibits Hypoxia Signaling Pathways And 3D Spheroid Growth Of Cancer Cells</p>

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