Figure 1.

Hypoxia-regulated human erythropoietin (EPO) gene expression in neuronal and liver cells. Hypoxia leads to stabilization of hypoxia-inducible factor (HIF), and mainly HIF-2 containing complexes are able to induce EPO gene expression. In neuronal cells, HIF-containing complexes bind most strongly to the newly identified hypoxia response element (HRE) in the promoter and to a lesser extent to the 3'-HRE. Although HIF-complexes appear not to bind the 5'-HRE, the 5´-HRE co-operates in the hypoxic induction process. In liver cells, HIF-complexes bind mainly to the 3´-HRE, weakly to the pHRE, and not to the 5´- HRE. Lighter colors indicate less HIF binding; green arrows indicate co-operation between the HREs. KIE: kidney-inducible element; NRE: negative regulatory element; LIE: liver-inducible element; HRE: hypoxia response element; NRLE: negative regulatory liver element; Prom: promoter; pHRE: promoter HRE functioning as one entity but consisting of a tandem dimeric repeat with two HRE sequences.