Fig. 2— Hypoxia-inducible factor (HIF)-1-mediated oxygen sensing of transcription. The schematic illustrates how the α-subunit of the heterodimeric transcription factor HIF-1 conveys hypoxic conditions to transcriptional control. a) Under hypoxic conditions, HIF-1α dimerises with HIF-1β and binds to HIF-responsive target genes, such as erythropoietin or vascular endothelial growth factor. After recruitment of the transcriptional coactivator CREB (cAMP response element binding)-binding protein (CBP)/p300 to HIF-1α and additional binding of gene- or tissue-specific transcriptional cofactors, HIF-1-dependent transcription is induced. b) Under normoxic conditions, HIF-1α is absent because it is inactivated and immediately degraded by the proteasomal machinery. The oxygen sensors translating the oxygen concentration into changes in HIF-1α are oxygen-dependent hydroxylases: factor inhibiting HIF-1 (FIH-1) and prolyl hydroxylase domain-containing proteins 1–3 (PHDs). In the presence of oxygen, FIH-1 hydroxylates asparaginyl residue 803 (N) within the C-terminal transactivation domain of HIF-1α, preventing the recruitment of CBP/p300 to the HIF-1 complex, which leads to reduction of transcriptional activity. PHDs hydroxylate two prolyl (P) residues (P402 and P564) within the oxygen-dependent degradation domain of HIF-1α, allowing binding of the von Hippel–Lindau tumour suppressor protein (pVHL). pVHL functions as a recognition element for the multiprotein E3 ubiquitin ligase complex, which targets HIF-1α, via polyubiquitination, for proteasomal degradation. Whereas dimerisation and transactivation of the HIF-1 complex takes place in the cell nuclei, it is still under discussion whether the oxygen sensing process of FIH-1/PHDs, the binding of pVHL and the proteasomal degradation can take place in both cytoplasm and nucleus. OH: hydroxyl group.