Cellular response to hypoxia

Stable Identifier
Homo sapiens
Regulation of Hypoxia-inducible Factor (HIF) by oxygen
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Oxygen plays a central role in the functioning of human cells: it is both essential for normal metabolism and toxic. Here we have annotated one aspect of cellular responses to oxygen, the role of hypoxia-inducible factor in regulating cellular transcriptional responses to changes in oxygen availability.

In the presence of oxygen members of the transcription factor family HIF-alpha, comprising HIF1A, HIF2A (EPAS1), and HIF3A, are hydroxylated on proline residues by PHD1 (EGLN2), PHD2 (EGLN1), and PHD3 (EGLN3) and on asparagine residues by HIF1AN (FIH) (reviewed in Pouyssegur et al. 2006, Semenza 2007, Kaelin and Ratcliffe 2008, Nizet and Johnson 2009, Brahimi-Horn and Pouyssegur 2009, Majmundar et al. 2010, Loenarz and Schofield 2011). Both types of reaction require molecular oxygen as a substrate and it is probable that at least some HIF-alpha molecules carry both hydroxylated asparagine and hydroxylated proline (Tian et al. 2011).
Hydroxylated asparagine interferes with the ability of HIF-alpha to interact with p300 and CBP while hydroxylated proline facilitates the interaction of HIF-alpha with the E3 ubiquitin ligase VHL, causing ubiquitination and proteolysis of HIF-alpha. Hypoxia inhibits both types of hydroxylation, resulting in the stabilization of HIF-alpha, which then enters the nucleus, binds HIF-beta, and recruits p300 and CBP to activate target genes such as EPO and VEGF.

Literature References
PubMed ID Title Journal Year
15304631 Hydroxylation of HIF-1: oxygen sensing at the molecular level

Semenza, GL

Physiology (Bethesda) 2004
19339544 HIF at a glance

Brahimi-Horn, MC, Pouysségur, J

J Cell Sci 2009
16724055 Hypoxia signalling in cancer and approaches to enforce tumour regression

Mazure, NM, Pouysségur, J, Dayan, F

Nature 2006
19704417 Interdependence of hypoxic and innate immune responses

Nizet, V, Johnson, RS

Nat Rev Immunol 2009
20728359 Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases

Schofield, CJ, Loenarz, C

Trends Biochem Sci 2011
17916722 Life with oxygen

Semenza, GL

Science 2007
20965423 Hypoxia-inducible factors and the response to hypoxic stress

Wong, WJ, Simon, MC, Majmundar, AJ

Mol Cell 2010
21335549 Differential sensitivity of HIF hydroxylation sites to hypoxia and hydroxylase inhibitors

Willam, C, Lee, MK, Yeoh, KK, Tian, YM, Edelmann, MJ, Kessler, BM, Kramer, HB, Schofield, CJ, Pugh, CW, Ratcliffe, PJ, Eriksson, T

J Biol Chem 2011
18498744 Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway

Kaelin WG, Jr, Ratcliffe, PJ

Mol Cell 2008
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