Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Jun 15;66(6):772-779.
doi: 10.1016/j.molcel.2017.06.002.

The EGLN-HIF O2-Sensing System: Multiple Inputs and Feedbacks

Mircea Ivan  1 , William G Kaelin Jr  2
Affiliations
Review

The EGLN-HIF O2-Sensing System: Multiple Inputs and Feedbacks

Mircea Ivan et al. Mol Cell. .

Abstract

The EGLN (also called PHD) prolyl hydroxylase enzymes and their canonical targets, the HIFα subunits, represent the core of an ancient oxygen-monitoring machinery used by metazoans. In this review, we highlight recent progress in understanding the overlapping versus specific roles of EGLN enzymes and HIF isoforms and discuss how feedback loops based on recently identified noncoding RNAs introduce additional layers of complexity to the hypoxic response. Based on novel interactions identified upstream and downstream of EGLNs, an integrated network connecting oxygen-sensing functions to metabolic and signaling pathways is gradually emerging with broad therapeutic implications.

Keywords: EGLN; HIF1α; HIF2α; PHD; hypoxia; lncRNA; metabolism; miRNA; noncoding RNA; oxygen.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Model of cooperation between coding genes and miR-210 downstream of HIF1. Feedback loop leading to renormalization of local O2 tension as a result of decreased local consumption.
Figure 2
Figure 2
Model of noncoding RNA-based feedback circuits optimizing the transition from a HIF1 to a HIF2-based hypoxic response.
See this image and copyright information in PMC

References

    1. Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, Ratcliffe PJ, Gleadle JM. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem. 2004;279:38458–38465. - PubMed
    1. Balsa E, Marco R, Perales-Clemente E, Szklarczyk R, Calvo E, Landazuri MO, Enriquez JA. NDUFA4 is a subunit of complex IV of the mammalian electron transport chain. Cell Metab. 2012;16:378–386. - PubMed
    1. Berra E, Benizri E, Ginouves A, Volmat V, Roux D, Pouyssegur J. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J. 2003;22:4082–4090. - PMC - PubMed
    1. Bigham AW, Lee FS. Human high-altitude adaptation: forward genetics meets the HIF pathway. Genes Dev. 2014;28:2189–2204. - PMC - PubMed
    1. Briggs KJ, Koivunen P, Cao S, Backus KM, Olenchock BA, Patel H, Zhang Q, Signoretti S, Gerfen GJ, Richardson AL, et al. Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine. Cell. 2016;166:126–139. - PMC - PubMed

MeSH terms