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Figure 1 | Cancer & Metabolism

Figure 1

From: Hypoxia signaling pathways in cancer metabolism: the importance of co-selecting interconnected physiological pathways

Figure 1

Regulation of HIF-1 by oxygen dependent prolyl and asparaginyl hydroxylation of HIF-1α. Hypoxia inducible factor (HIF)-1α, a basic-Helix-Loop-Helix Per-AHR/ARNT/Sim (bHLH-PAS) domain containing protein, contains three residues that are targets for regulatory hydroxylation. P402 and P564 are targeted by the prolyl hydroxylase domain (PHD) enzymes (note that PHD3 can only hydroxylate P564) and N803 by factor inhibiting HIF (FIH). P402 is located in the N-terminal, and P564 in the C-terminal, O2-dependent degradation domain. Prolyl hydroxylated HIF-1α is recognized by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex, leading to degradation in normoxia. Interestingly, prolyl and asparaginyl hydroxylation are differentially sensitive to hypoxia. Inhibition of prolyl hydroxylation alone (lower right) is sufficient to allow HIF-1α to escape from pVHL E3-dependent proteolytic destruction and form an active transcriptional complex with HIF-β through activity of the N-terminal activation domain (NAD). In more severe hypoxia, HIF-1α asparaginyl hydroxylation is also inhibited (lower left) allowing recruitment of p300/CBP co-activators to its C-terminal transactivation domain (CAD), and enhancing the transcription of a specific set of HIF-1 target genes. (HRE, hypoxia-response element).

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