Oxygen sensing and hypoxia signalling pathways in animals: the implications of physiology for cancer

Abstract

Studies of regulation of the haematopoietic growth factor erythropoietin led to the unexpected discovery of a widespread system of direct oxygen sensing that regulates gene expression in animals. The oxygen-sensitive signal is generated by a series of non-haem Fe(II)- and 2-oxoglutarate-dependent dioxygenases that catalyse the post-translational hydroxylation of specific residues in the transcription factor hypoxia-inducible factor (HIF). These hydroxylations promote both oxygen-dependent degradation and oxygen-dependent inactivation of HIF, but are suppressed in hypoxia, leading to the accumulation of HIF and assembly of an active transcriptional complex in hypoxic cells. Hypoxia-inducible factor activates an extensive transcriptional cascade that interfaces with other cell signalling pathways, microRNA networks and RNA-protein translational control systems. The relationship of these cellular signalling pathways to the integrated physiology of oxygen homeostasis and the implication of dysregulating these massive physiological pathways in diseases such as cancer are discussed.

Figure 1. Schematic diagram illustrating the dual regulation of hypoxia-inducible factor (HIF) by oxygen-dependent prolyl and asparaginyl hydroxylation

Pro, proline; OH Pro, hydroxyproline; Asn, asparagine; Asn OH, hydroxyasparagine; p300/CBP, E1A binding protein p300/CREB-binding protein.

Figure 2. The catalytic iron centre of a typical 2-oxoglutarate (2-OG)-dependent dioxygenase

Of six co-ordinate positions, three are used to bind the 2-histidine-1-carboxylate ‘facial triad’ of the apo-enzyme, two are used to bind the cosubstrate 2-oxoglutarate and the sixth is occupied by a water molecule or (upon activation of the enzyme) molecular oxygen. Potentially, these interactions provide signalling interfaces with molecular oxygen, redox stresses and metabolism.

Figure 3. The principle of ‘range finding’ processes that match HIF prolyl hydroxylation to the rate of synthesis of HIF and to the capacity of HIF degradation pathways downstream of hydroxylation

NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; mTOR, mammalian target of rapamycin.

Figure 4. Coselection of extensive hard-wired physiological pathways in cancer

Oncogenic mutations (A) and (B) provide a cell with autonomous advantage, hence oncogenic drive, but are physiologically linked to pathways whose activation is supportive, neutral, restrictive or even lethal.

Figure 5

Implications of the physiological ‘coselection penalty’ in cancer