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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.

This Collection is editorially independent, produced with financial support from a third party. About this content.

From the winners

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.

Letter | | Nature

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.

Opinion | | Nature Reviews Cancer

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.

Article | Open Access | | Nature Communications

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.

News & Views | | Nature Structural & Molecular Biology

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.

Review Article | | Nature Reviews Nephrology

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.

Letter | | Nature Genetics

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.

Article | | Nature Genetics

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.

News & Views | | Nature Cell Biology

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.

Letter | | Nature Cell Biology

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.

Letter | | Nature

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.

News and Views Q&A | | Nature

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.

Article | Open Access | | Nature Communications

Research

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | | Nature Chemical Biology

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

Reviews and Comment

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.

Timeline | | Nature Reviews Cancer

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.

Review Article | | Nature Reviews Drug Discovery

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.

Review Article | | Nature Reviews Gastroenterology & Hepatology

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.

News & Views | | Nature Reviews Nephrology

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.

Review Article | | Nature Reviews Rheumatology

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.

Review Article | | Nature Reviews Rheumatology

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.

News & Views | | Nature Reviews Nephrology

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.

Comment | | Nature Metabolism