Figure 2.

Regulation of HIF signaling in metazoan cells. HIFs are a kind of heterodimeric transcription factors that comprise an α subunit (O₂-sensitive) and a β subunit (constitutive). Under normoxia, proline residues in the ODD of HIF-α are hydroxylated by PHDs or FIH, which facilitates HIF-α binding to the VHL E3 ubiquitin ligase complex, and leads to polyubiquitination and proteosomal degradation. Hypoxia induces HIF-α protein stabilization by inactivating PHD and FIH. Activated HIF-α translocates from the cytoplasm to the nucleus, where it dimerizes with HIF-1β and recruits CBP/p300, and then binds to HRE (5’-RCGTG-3’) in the promoter or enhancer of HIF-regulated genes [including PCGs, hypoxia-responsive lncRNAs (HRLs) and hypoxamiRs], finally regulate a variety of hypoxia-adaptive pathways such as angiogenesis, anaerobic metabolism, and erythropoiesis.