The receptor tyrosine kinase HIR-1 coordinates HIF-independent responses to hypoxia and extracellular matrix injury

Vozdek, Roman; Long, Yong; Dengke, K.

doi:10.1126/scisignal.aat0138

Cited by 23 publications

(26 citation statements)

References 73 publications

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“…Collectively these data show that nhr-49 is a core part of a hypoxia response pathway that is independent of hif-1 signalling. In support of our study, a recent publication (Vozdek et al, 2018) showed that nhr-49 is required to induce the hif-1-independent hypoxia response gene comt-5 both in 0.5% O2 and in a strain mutant for the kinase hir-1. In hypoxia, HIR-1 coordinates remodeling of the extracellular matrix independently of HIF-1 (Vozdek et al, 2018).…”

Section: Nhr-49 Controls a Novel Hypoxia Response Pathway That Is Parsupporting

confidence: 89%

“…In support of our study, a recent publication (Vozdek et al, 2018) showed that nhr-49 is required to induce the hif-1-independent hypoxia response gene comt-5 both in 0.5% O2 and in a strain mutant for the kinase hir-1. In hypoxia, HIR-1 coordinates remodeling of the extracellular matrix independently of HIF-1 (Vozdek et al, 2018). Thus, although our RNA-seq results did not identify comt-5 as a target of NHR-49 in hypoxia, this study supports the idea of a hif-1independent hypoxia response pathway involving nhr-49.…”

Section: Nhr-49 Controls a Novel Hypoxia Response Pathway That Is Parsupporting

confidence: 89%

“…The copyright holder for this preprint this version posted February 24, 2021. ; https://doi.org/10.1101/2021.02.24.432575 doi: bioRxiv preprint Doering et al Hypoxia 5 required to increase expression of the Catechol-O-Methyl-Transferase comt-5 downstream of the Hypoxia Inhibited Receptor tyrosine kinase hir-1, which mediates extracellular matrix remodelling in hypoxia (Vozdek et al, 2018). However, the role of nhr-49 in hypoxia and how it intersects with hif-1 have not been explored.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to regulating lipid metabolism, NHR-49 also regulates putative xenobiotic detoxification genes in a dietary restriction-like state and during starvation (Chamoli et al, 2014;Goh et al, 2018), is required for resistance to oxidative stress (Goh et al, 2018), and activates innate immune response programs upon infection of C. elegans with Staphylococcus aureus (Wani et al, 2020), Pseudomonas aeruginosa (Naim et al, 2020), and Enterococcus faecalis (Dasgupta et al, 2020). Moreover, a recent report showed that nhr-49 is required to increase expression of the Catechol-O-Methyl-Transferase comt-5 downstream of the Hypoxia Inhibited Receptor tyrosine kinase hir-1, which mediates extracellular matrix remodelling in hypoxia (Vozdek et al, 2018). However, the role of nhr-49 in hypoxia and how it intersects with hif-1 have not been explored.…”

Section: Introductionmentioning

confidence: 99%

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Nuclear Hormone Receptor NHR-49 controls a HIF-1-independent hypoxia adaptation pathway inCaenorhabditis elegans

Doering

Cheng

Milburn

et al. 2021

Preprint

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The response to insufficient oxygen (hypoxia) is orchestrated by the conserved Hypoxia-Inducible Factor (HIF). However, HIF-independent hypoxia response pathways exist that act in parallel to HIF to mediate the physiological hypoxia response. Here, we describe a HIF-independent hypoxia response pathway controlled by Caenorhabditis elegans Nuclear Hormone Receptor NHR-49, an orthologue of mammalian Peroxisome Proliferator-Activated Receptor alpha (PPARα). We show that nhr-49 is required for worm survival in hypoxia and is synthetic lethal with hif-1 in this context, demonstrating that these factors act independently. RNA-seq analysis shows that in hypoxia nhr-49 regulates a set of genes that are hif-1-independent, including autophagy genes that promote hypoxia survival. We further show that Nuclear Hormone Receptor nhr-67 is a negative regulator and Homeodomain-interacting Protein Kinase hpk-1 is a positive regulator of the NHR-49 pathway. Together, our experiments define a new, essential hypoxia response pathway that acts in parallel to the well-known HIF-mediated hypoxia response.

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Section: Nhr-49 Controls a Novel Hypoxia Response Pathway That Is Parsupporting

confidence: 89%

Section: Nhr-49 Controls a Novel Hypoxia Response Pathway That Is Parsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Nuclear Hormone Receptor NHR-49 controls a HIF-1-independent hypoxia adaptation pathway inCaenorhabditis elegans

Doering

Cheng

Milburn

et al. 2021

Preprint

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“…Currently, we do not know the alteration in cellular behavior that hypoxia triggers to render cells less responsive to YM155. Although HIFs represent the best-studied mechanism by which hypoxia impacts cellular responses through gene regulation, many reports confirm the critical roles of HIF-independent cellular responses to hypoxia ( Vozdek et al., 2018 ; Fortenbery et al., 2018 ; Ahmed et al., 2018 ; Park et al., 2016 ). Importantly, a recent study provided strong evidence that hypoxia re-programs global changes in gene expression by rapidly modifying chromatin methylation through a HIF-independent mechanism ( Batie et al., 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia represses early responses of prostate and renal cancer cells to YM155 independent of HIF-1α and HIF-2α

Danielpour

Corum²,

Welford

et al. 2022

Current Research in Pharmacology and Drug Discovery

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The imidazolium compound Sepantronium Bromide (YM155) successfully promotes tumor regression in various pre-clinical models but has shown modest responses in human clinical trials. We provide evidence to support that the hypoxic milieu of tumors may limit the clinical usefulness of YM155. Hypoxia (1% O 2 ) strongly (>16-fold) represses the cytotoxic activity of YM155 on prostate and renal cancer cells in vitro . Hypoxia also represses all early signaling responses associated with YM155, including activation of AMPK and retinoblastoma protein (Rb), inactivation of the mechanistic target of rapamycin complex 1 (mTORC1), inhibition of phospho-ribosomal protein S6 (rS6), and suppression of the expression of Cyclin Ds, Mcl-1 and Survivin. Cells pre-incubated with hypoxia for 24 h are desensitized to YM155 even when they are treated with YM155 under atmospheric oxygen conditions, supporting that cells at least temporarily retain hypoxia-induced resistance to YM155. We tested the role of hypoxia-inducible factor (HIF)-1α and HIF-2α in the hypoxia-induced resistance to YM155 by comparing responses of YM155 in VHL-proficient versus VHL-deficient RCC4 and 786-O renal cancer cells and silencing HIF expression in PC-3 prostate cancer cells. Those studies suggested that hypoxia-induced resistance to YM155 occurs independent of HIF-1α and HIF-2α. Moreover, the hypoxia mimetics deferoxamine and dimethyloxalylglycine, which robustly induce HIF-1α levels in PC-3 cells under atmospheric oxygen, did not diminish their early cellular responses to YM155. Collectively, our data support that hypoxia induces resistance of cells to YM155 through a HIF-1α and HIF-2α-independent mechanism. We hypothesize that a hypothetical hypoxia-inducer factor (HIF-X) represses early signaling responses to YM155.

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Vascular characteristics and expression of hypoxia genes in Tibetan pigs’ hearts

Yang

Gao

Yang

et al. 2021

Veterinary Medicine & Sci

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Background: Tibetan pigs have exhibited unique characteristics from low-altitudes pigs and adapted well to the Qinghai-Tibet Plateau. Objectives:The current study was undertaken to investigate the hypoxic adaptation of heart in Tibetan pigs. Methods:The hearts of Tibetan pigs and Landrace pigs raised at high or low altitudes were compared using 3D casting technology, scanning electron microscopy and realtime quantitative PCR (qRT-PCR). Results:We found that the ratio of the major axis to the minor axis and the density of the heart were significantly higher in Tibetan pigs than in Landrace pigs (p < 0.05).Tibetan pigs had larger diameters and higher densities of arterioles than Landrace pigs (p < 0.05), and these features have a similar variation with the expression of vascular endothelial growth factor (VEGF). The cardiac expression levels of hypoxia-inducible factor-1α (HIF-1α) and endothelial nitric oxide synthase (eNOS) were significantly higher in pigs reared at high altitudes than in those reared at low altitudes (p < 0.05).In contrast, Egl nine homolog 1 (EGLN1) had the opposite trend with respect to HIF-1α and eNOS and was related to red blood cell (RBC) counts. Notably, the expressions of erythropoietin (EPO) and endothelial PAS domain-containing protein 1 (EPAS1) were significantly higher in Landrace pigs kept at high altitudes than in the others (p < 0.05) and were associated with haemoglobin.Conclusions: These findings show that the regulation of the heart function of Tibetan pigs in a hypoxic environment is manifested at various levels to ensure the circulation of blood under extreme environmental conditions.

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The receptor tyrosine kinase HIR-1 coordinates HIF-independent responses to hypoxia and extracellular matrix injury

Cited by 23 publications

References 73 publications

Nuclear Hormone Receptor NHR-49 controls a HIF-1-independent hypoxia adaptation pathway inCaenorhabditis elegans

Nuclear Hormone Receptor NHR-49 controls a HIF-1-independent hypoxia adaptation pathway inCaenorhabditis elegans

Hypoxia represses early responses of prostate and renal cancer cells to YM155 independent of HIF-1α and HIF-2α

Vascular characteristics and expression of hypoxia genes in Tibetan pigs’ hearts

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