Figure 2.

Hypoxia inducible transcription factor regulation. Under normal oxygen conditions hypoxia-inducible factor-1α (HIF-1α) is hydroxylated by prolyl hydroxylase (PHD) enzymes and targeted for ubiquitination by the Von Hippel-Lindau tumor suppresser ubiquitin ligase complex (pVHL). During hypoxia or low oxygen conditions, HIF-1α is stabilized, translocates to the nucleus and associates with HIF-β to promote gene expression, targeting genes containing a hypoxia response element (HRE). HIF-1α acts as a glycolytic enhancer through transcriptional activation of metabolic genes including 6-phosphofructo-2-kinase/fructose-2,6-bisphosphate 3 (PFKFB3) and pyruvate dehydrogenase kinase-1 (PDK1), both positive regulators of glycolysis and monocarboxylate transporter 4 (MCT4), the lactate efflux transporter. Ub, ubiquitin; OH, hydroxyl group.