Fig. 5. This scheme represents the current concept for hypoxia-inducible factor-1 (HIF-1) pathways. In normoxic conditions, HIF-1 is continuously produced and, in the presence of Fe²⁺ and oxygen, is continuously degraded through the Von Hippel Lindau protein (VHL)/Ubiquitin/Proteosome pathway. When oxygen becomes limiting, prolyl hydroxylase is inhibited and HIF-1 accumulates. After translocation and combination with the constitutive HIF-1, the transcription factor binds to hypoxic response element (HRE) sequences to upregulate a number of downstream genes such as erythropoietin (EPO), VEGF, lactate dehydrogenase (LDH), inducible nitric oxide synthase (iNOS), GLUT-1 and enolase-1 (ENO). (Drawing by Max Neal.)