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Nobel Prize in Physiology or Medicine 2019
This collection of research, review and comment from Nature Research celebrates the 2019 Nobel Prize in Physiology or Medicine awarded to William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza “for their discoveries of how cells sense and adapt to oxygen availability”. The ability of organisms to respond to changes in oxygen availability is of fundamental importance to life on earth. Work by the prize-winning scientists has shown that in animal cells, oxygen availability affects gene expression through oxygen-sensitive post-translational modification and the subsequent proteasomal degradation of Hypoxia Inducible Factors. This research laid the foundation for understanding the mechanistic basis for the cellular response to hypoxia and paved the way for the therapeutic targeting of the response pathway to treat conditions including cancer and anaemia.
All research papers under ‘From the winners’ are free to access until April 2020.
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From the winners
On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models
The transcription factor HIF-2, an important driver of clear cell renal cell carcinoma, has been called 'undruggable'. However, in this issue of Nature, two groups report on the development and testing of a novel HIF-2α inhibitor, termed PT2399. William Kaelin and colleagues show that PT2399 causes tumour regression in preclinical mouse models of primary and metastatic pVHL-defective clear cell renal cell carcinoma. James Brugarolas and colleagues tested the compound in mice with tumour grafts generated from human renal cell cancers. PT2399 decreased tumour growth in 10 out of 18 cell lines and was well tolerated. The authors identify potential markers of sensitivity and provide initial characterization of the effects and mechanisms of resistance acquisition in vivo. Both groups report variable sensitivity to PT2399 in some pVHL-defective cell lines, highlighting a need for predictive biomarkers to be developed for use of this approach in the clinic.
Hypoxia and the extracellular matrix: drivers of tumour metastasis
Emerging data indicate that hypoxia and the extracellular matrix (ECM) together might have a crucial role in metastasis. In this Opinion article the authors suggest a model in which multiple microenvironmental signals might converge to synergistically influence metastatic outcome.
Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases
The response to hypoxia involves multiple genes regulated by the hypoxia inducible transcription factors (HIFs), whose stability is regulated by prolyl hydroxylation. Here the authors provide a molecular basis for the substrate selectivity of the HIF prolyl hydroxylases that can be altered in erythrocytosis and cancer.
ExCITED about HIF
The structure of the CH1 domain of p300 in complex with the transactivation domain of CITED2 brings us one step closer toward understanding the molecular basis of the regulation of hypoxia response.
Mechanisms of hypoxia signalling: new implications for nephrology
Therapeutic modulation of hypoxia-inducible factors, which transduce adaptive transcriptional responses to hypoxia, is an emerging theme in kidney disease. This Review summarizes the hypoxia signalling mechanisms underpinning these novel treatments and highlights key remaining questions relevant to their clinical use.
Oxygenase-catalyzed ribosome hydroxylation occurs in prokaryotes and humans
The identification of Escherichia coli ycfD and human MINA53 and NO66 as ribosomal amino acid hydroxylases defines a role for 2-oxoglutarate/iron-dependent oxygenases in translational regulation.
Common genetic variants at the 11q13.3 renal cancer susceptibility locus influence binding of HIF to an enhancer of cyclin D1 expression
Johannes Schödel and colleagues report the identification of a distant transcriptional enhancer of CCND1 at the recently identified renal cell carcinoma susceptibility locus at 11q13.3. The protective haplotype shows reduced binding of HIF-2α, reduced interaction with the transcriptional machinery and allelic imbalance in CCND1 expression. The study suggests that the hypoxia pathway is misregulated in renal cell carcinoma development.
Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer
Genome-wide association studies have identified multiple loci associated with the risk of developing renal cancer. Here, the authors show that one of these loci generates open chromatin, which enhances the binding of HIF and HIF-mediated transactivation ofMYC.
A genetic mechanism for Tibetan high-altitude adaptation
Josef Prchal and colleagues identify a mutation in EGLN1 associated with adaptation to high altitude in Tibetan individuals. Their functional studies suggest a mechanism acting to reduce the erythropoietic response to hypoxia.
New insights into an enigmatic tumour suppressor
Dynamic regulation of the microtubule apparatus is central to cell division, cell migration, polarity and transport. New data demonstrating functional association of the von Hippel-Lindau (VHL) tumour suppressor with microtubules provide a new lead in unravelling VHL tumour suppressor mechanisms.
Common pitfalls in preclinical cancer target validation
This Perspective discusses some of the causes of the robustness and reproducibility problem in preclinical cancer research and suggests solutions.
The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity
Oxygen levels regulate the stability of the transcription factor HIF-1 through the action of prolyl hydroxylases and the VHL ubiquitin ligase. Sharp and colleagues now identify a protein complex in which the Ajuba LIM-domain protein LIMD1 brings together prolyl hydroxylases and VHL to ensure efficient degradation of HIF-1.
The Jumonji-C oxygenase JMJD7 catalyzes (3S)-lysyl hydroxylation of TRAFAC GTPases
Structural, biochemical and cellular studies reveal JMJD7 to be a Jumonji-C oxygenase that catalyzes (3S)-lysyl hydroxylation of the translation factor family of GTPases, DRG1 and DRG2.
Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation
Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 have been identified in gliomas, the most common form of brain tumour, and in other cancers including leukaemias. The mutated enzymes produce 2-hydroxyglutarate (2HG), which is a potential oncometabolite. Three papers in this issue of Nature examine the mechanisms through which IDH mutations promote cancers. Lu et al. show that 2HG-producing IDH mutants can prevent the histone demethylation that is required for progenitor cells to differentiate, potentially contributing to tumour-cell accumulation. Turcan et al. show that IDH1 mutation in primary human astrocytes induces DNA hypermethylation and reshapes the methylome to resemble that of the CIMP phenotype, a common feature of gliomas and other solid tumours. Koivunen et al. show that the (R)-enantiomer of 2HG (but not the (S)-enantiomer) can stimulate the activity of the EGLN prolyl 4-hydroxylases, leading to diminished levels of hypoxia-inducible factor (HIF), which in turn can enhance cell proliferation. These papers establish a framework for understanding gliomagenesis and highlight the interplay between genomic and epigenomic changes in human cancers.
Clues from cell metabolism
Interest in the abnormal metabolism exhibited by cancer cells has been reawakened by the discovery of oncogenic mutations in metabolic enzymes, and by tools that monitor metabolism in living cells. Existing and emerging therapies aim to target this abnormal metabolism in various ways.
Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution
Papillary renal cell carcinoma (pRCC) is a subtype of kidney cancer characterized by highly variable clinical behaviour. Here the authors sequence either the genomes or exomes of 31 pRCCs and identify several genes in sub-clones and large copy number variants in major clones that may be important drivers of pRCC.
A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension
Pulmonary hypertension is characterized by a metabolic switch similar to the Warburg effect in cancer. Here Dabral et al. describe a RASSF1a-HIF-1α feedforward loop driving the Warburg effect both in a mouse model of hypoxia-induced pulmonary hypertension and a subset of human cancer cells.
Publish houses of brick, not mansions of straw
Papers need to include fewer claims and more proof to make the scientific literature more reliable, warns William G. Kaelin Jr.
Research
Hypoxia-specific ultrasensitive detection of tumours and cancer cells in vivo
As hypoxia is a hallmark of tumour microenvironment, hypoxia-sensing probes are used for tumour imaging. Here, the authors report a hypoxia probe with increased sensitivity, water solubility and functional pH range, allowing in vivodetection of early metastases as small as a few thousand cells.
Human 3D cellular model of hypoxic brain injury of prematurity
Brain organoids derived from human iPSCs are used to study the effects of hypoxia on early cortical neurodevelopment and identify defects in specific human progenitor populations that likely contribute to encephalopathy of prematurity.
Characterization of hypoxia-associated molecular features to aid hypoxia-targeted therapy
The conventional view holds that hypoxia confers drug resistance. In contrast, here the authors use a multilayer ‘omics data approach to characterize the molecular features associated with tumour hypoxia and identify molecular alterations that correlate with both drug-resistant and drug-sensitive responses to approved drugs.
miR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS
Wu et al. find that tumour hypoxic conditions increase miR25/93 levels, which via targeting Ncoa3 downregulate the expression of the innate immune regulator cGAS, thus allowing escape of the anti-tumour immune response.
Plant cysteine oxidases control the oxygen-dependent branch of the N-end-rule pathway
Oxygen sensing in plants is mediated by the N-end rule pathway, in which the N-terminal cysteine residue of ERF-VII transcription factors is selectively oxidised. Weits et al.identify cysteine oxidases responsible for this modification, and show that their expression is itself regulated by ERF-VII.
A three-dimensional engineered heterogeneous tumor model for assessing cellular environment and response
This protocol describes TRACER, a 3D cell culture system that enables the assembly of heterogeneous model tumors or tissues that easily disassemble for rapid analysis of different cell populations from particular microenvironments.
Refined control of cell stemness allowed animal evolution in the oxic realm
The earliest animal diversification has been associated with increased oxygenation. Here an alternative model is proposed: hypoxia-inducible transcription factors gave animals unprecedented control of cell stemness that allowed them to cope with fluctuating oxygen concentrations.
Bidirectional modulation of HIF-2 activity through chemical ligands
Structural analysis of HIF-2α in complex with agonists and antagonists reveal that chemical ligands regulate the activity of HIF-2α by affecting the stability of the HIF-2α–ARNT heterodimer via redirecting residues in the PAS-B pocket.
Allosteric inhibition of hypoxia inducible factor-2 with small molecules
A new small-molecule inhibitor that selectively binds an internal cavity in HIF-2α allosterically disrupts HIF-2α–ARNT interaction in vitro and in cells. This compound should allow scientists to interrogate HIF-2α's activity in hypoxia and cancer cells.
Osteocytic oxygen sensing controls bone mass through epigenetic regulation of sclerostin
Osteocytes reside in a low oxygen environment, but it is not clear if oxygen sensing regulates their function. Here, the authors show that deletion of the oxygen sensor prolyl hydroxylase 2 in osteocytes leads to increased bone mass via regulation of sclerostin, and reduces bone loss in mouse models of osteoporosis.
TRPA1 underlies a sensing mechanism for O2
The redox-sensitive TRP channel TRPA1 is activated in hyperoxic and hypoxic conditions directly through modification of cysteine residues by O2 and indirectly through prolyl hydroxylation by PHDs, enzymes related to the hypoxia-inducible factor HIF-1, thus helping to explain how O2 is sensed by sensory and vagal neurons.
Mitochondrial protein E2F3d, a distinctive E2F3 product, mediates hypoxia-induced mitophagy in cancer cells
Keigo Araki and colleagues show that E2F3d, a previously unidentified isoform of transcription factor E2F3, mediates hypoxia-induced mitophagy in cancer cells. This study discovers another mitophagy receptor that regulates mitochondrial quality control.
Activation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis
Obesity induces hypoxia and upregulation of HIF-2α in the gastrointestinal tract, resulting in excess ceramide production and exacerbation of NAFLD.
Negative regulation of Hif1a expression and TH17 differentiation by the hypoxia-regulated microRNA miR-210
Hypoxia stabilizes the transcription factor HIF-1α, which promotes TH17 polarization. Weiss and colleagues show that miR-210 mediates a negative feedback regulatory loop that diminishes HIF-1α abundance under hypoxic conditions.
TORC1 modulation in adipose tissue is required for organismal adaptation to hypoxia in Drosophila
The hypoxia response pathway couples oxygen availability to physiological adaptations. Using the model system Drosophila melanogaster, here the authors show that hypoxia inhibits TORC1 signalling and increases lipid levels in the larval fat body and that these effects are required for development to adulthood.
Hypoxia-inducible factor–dependent induction of netrin-1 dampens inflammation caused by hypoxia
Hypoxia incites inflammation, particularly at mucosal surfaces. Eltzschig and colleagues show that hypoxia also suppresses inflammation by inducing expression of the neuronal guidance molecule netrin-1, which inhibits the transepithelial migration of neutrophils.
Plant cysteine oxidases are dioxygenases that directly enable arginyl transferase-catalysed arginylation of N-end rule targets
The N-end rule pathway targets substrate proteins for proteasomal degradation. Here, Whiteet al. show that ArabidopsisPLANT CYSTEINE OXIDASEs show dioxygenase activity producing Cys-sulfinic acid at the N-terminus of target proteins, which then act as direct substrates for arginyl transferase.
A hypoxia-responsive TRAF6–ATM–H2AX signalling axis promotes HIF1α activation, tumorigenesis and metastasis
Lin and colleagues report that hypoxia induces TRAF6-dependent mono-ubiquitylation of histone H2AX, which promotes binding and stabilization of HIF1α. Activated HIF1α signalling in turn promotes tumorigenesis and metastasis.
A fat-tissue sensor couples growth to oxygen availability by remotely controlling insulin secretion
The mechanisms by which organisms adapt their growth according to the availability of oxygen are incompletely understood. Here the authors identify the Drosophila fat body as a tissue regulating growth in response to oxygen sensing via a mechanism involving Hph inhibition, HIF1-a activation and insulin secretion.
Erythrocytes retain hypoxic adenosine response for faster acclimatization upon re-ascent
Humans that reach high altitude soon after the first ascent show faster adaptation to hypoxia. Songet al. show that this adaptive response relies on decreased red blood cell uptake of plasma adenosine due to reduced levels of nucleoside transporter ENT1 resulting from coordinated adenosine generation by ectonucleotidase CD73 and activation of A2B receptors.
Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen
The transcription factor HIF is induced in response to hypoxic stress, TCR activation and cytokines. Goldrath and colleagues show that HIF signaling enhances CTL effector responses and can render cells refractory to immune exhaustion.
Local lung hypoxia determines epithelial fate decisions during alveolar regeneration
Xi et al. show that after influenza infection, hypoxia drives Notch signalling to expand Krt5+ basal-like cells in the lung. On HIF1α loss, epithelial progenitors directly differentiate into alveolar type II cells and promote functional regeneration.
Reviews and Comment
VHL, the story of a tumour suppressor gene
The identification in 1993 of inherited mutations in the von Hippel–Lindau (VHL) gene in families with VHL disease was a seminal finding. This and subsequent discoveries have given the VHLtumour suppressor gene a central role in our understanding of the mechanisms of cellular oxygen sensing and in the pathobiology of clear-cell renal cell carcinoma.
Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases
Hypoxia-inducible factors (HIFs) have important roles in ischaemic and inflammatory diseases and strategies aimed at therapeutically modulating hypoxia signalling pathways are gaining considerable attention. Here, Eltzschig and colleagues focus on a set of oxygen-sensing prolyl hydroxylases — which are responsible for marking HIFs for proteasomal degradation — and assess their emerging potential as therapeutic targets.
Characterization of hypoxia-associated molecular features to aid hypoxia-targeted therapy
The conventional view holds that hypoxia confers drug resistance. In contrast, here the authors use a multilayer ‘omics data approach to characterize the molecular features associated with tumour hypoxia and identify molecular alterations that correlate with both drug-resistant and drug-sensitive responses to approved drugs.
Intestinal hypoxia and hypoxia-induced signalling as therapeutic targets for IBD
IBD is associated with markedly reduced intestinal mucosal oxygen levels. In this Review, the authors discuss the role of mucosal hypoxia and hypoxia-induced signalling in IBD and identify potential targets for therapies, focusing on the cell-specific functions of hypoxia-inducible factors, prolyl hydroxylases and nuclear factor-κB.
A new approach to treating renal anaemia
Erythropoiesis-stimulating agents (ESAs) are widely used to treat anaemia in patients with kidney disease. A potential alternative approach is to increase erythropoietin production using small-molecule inhibitors of prolyl hydroxylase domain (PHD) enzymes. Recent phase III trials of the PHD inhibitor roxadustat demonstrate similar efficacy and safety to ESAs.
Hypoxia—a key regulator of angiogenesis and inflammation in rheumatoid arthritis
The role of inflammation in rheumatoid arthritis (RA) is well characterized, but how hypoxia affects RA and the potential interplay between inflammation, angiogenesis and hypoxia in this disease is less defined. Here, the authors describe how hypoxia affects RA, in terms of both inflammation and angiogenesis, and provide insights as to how depleted oxygen levels affect the RA synovium. Potential therapies for RA that target angiogenesis will also be discussed.
Hypoxia-driven pathways in bone development, regeneration and disease
Oxygen is thought to be an indispensable regulatory signal in tissue development and homeostasis, via its controlling of specific genetic programs. Hypoxia-inducible transcription factors (HIFs), which are regulated by oxygen tension, are central mediators of the homeostatic response that enables cells to survive and differentiate in low-oxygen conditions. In this Review, the authors summarize the current knowledge of HIF signalling in cartilage, bone and blood, and pay particular attention to the complex relationship between HIF and VEGF in these tissues based on data collected from animal models, which can also be relevant in diseases like cancer and ischemia.
Oxygen sensing and cell metabolism in inflammation
Hypoxia-inducible transcription factors (HIFs) are key mediators of several molecular and cellular responses that are activated under hypoxic conditions. New findings demonstrate an important role for the HIF system in mediating the activation and inflammatory responses of neutrophils through tight interaction with their glucose metabolism.
Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis
In this article, the authors provide a comprehensive and timely review of the mechanisms and consequences of hypoxia in the biology of inflammatory arthritis, with a focus on mitochondrial function, hypoxia signalling pathways in rheumatoid arthritis, and therapeutic implications.
Control and dysregulation of redox signalling in the gastrointestinal tract
Redox signalling in the gastrointestinal mucosa is held in an intricate balance. This Review addresses both the spectrum and intensity of redox activity pertaining to host–immune and host–microbiota crosstalk during homeostasis and disease processes in the gastrointestinal tract.
Oxygen and mammalian cell culture: are we repeating the experiment of Dr. Ox?
Mammalian cell culture represents a cornerstone of modern biomedical research. There is growing appreciation that the media conditions in which cells are cultured can profoundly influence the observed biology and reproducibility. Here, we consider a key but often ignored variable, oxygen, and review why being mindful of this environmental parameter is so important in the design and interpretation of cell culture studies.
