Fig. 1

Hypoxia and signaling mediators. Representation of the signaling pathways mediated by NF-kB and HIF under normoxic and hypoxic conditions. Under normoxic conditions, HIF-α is hydroxylated by PHD and FIH enzymes to promote its ubiquitination and proteasomal degradation. During hypoxia, stabilized HIF-α relocates to the nucleus where it forms a dimer with HIF-β, recruits coactivators, and initiates transcription of hypoxia-regulated genes. NF-kB is inactive in the cytoplasm owing to its association with IkB. Activation of this pathway is regulated by IKK, which mediates the phosphorylation and degradation of IkB, allowing NF-kB to translocate to the nucleus where it activates gene transcription. PHD has been proposed to inhibit IKK under normoxic conditions. CoAct, coactivators; FIH, factor-inhibiting HIF (asparagyl β-hydroxylase); HIF, hypoxia-inducible factor; IkB, inhibitory protein; IKK, IkB kinase; NFkB, nuclear factor-kappa B; PHD, prolyl hydroxylase; vHL, von Hippel Lindau tumor suppressor