Schematic diagram of the HIF-signalling system and zebrafish homologues. Schematic diagram of the HIF-signalling system and zebrafish homologues. (A) Proteins of the HIF-signalling pathway are illustrated, with HIF proteins in green and proteins that target HIF for degradation in red. The human isoforms are listed, with their zebrafish counterparts in blue text. (B) In normoxia, the hydroxylase enzyme PHD and the VHL protein target HIF-α for ubiquitination in the cytoplasm and subsequent degradation by the proteasome. A second hydroxylase enzyme, FIH, hydroxylates a C-terminal asparagine residue on HIF-α in normoxia to repress the transactivation function of HIF. (C) In hypoxia, hydroxylase enzymes are silenced, and HIF translocates to the nucleus and binds its cofactors, where it upregulates target gene expression by binding to HREs in their regulatory regions. Abbreviations: CBP, CREB-binding protein; FIH, factor inhibiting HIF; HIF, hypoxia-inducible factor; HREs, HIF-responsive elements; P300, E1A binding protein; PHD, prolyl hydroxylase domain-containing proteins; VHL, von Hippel-Lindau. Philip M. Elks et al. Dis. Model. Mech. 2015;8:1349-1360 © 2015. Published by The Company of Biologists Ltd