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This hydroxylation serves as a recognition motif for the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex, leading to ubiquitination and subsequent proteasomal degradation of HIF-1 ( Figure 4 ), the activity of PHD enzymes is inhibited due to the lack of oxygen, an essential co-substrate for their enzymatic function ( Figure 4 Figure 5 The downstream effects of HIF activation are extensive and include upregulation of various genes and pathways ( Figure 6 ), involved in glycolysis, lactate shuttling & acid-base balance, Angiogenesis & Vascular Remodeling, erythropoiesis & iron metabolism, cell survival & stress response, lipid & amino acid metabolism and Immune Modulation ( Figure 6 Although HIF-2 shares structural similarity with HIF-1, it governs a distinct yet partially overlapping repertoire of target genes ( In contrast to HIF-1 and HIF-2, the biological functions of hypoxia-inducible factor-3 (HIF-3) are less well characterized and appear to be more context-dependent ( HIF3A gene and undergoes extensive alternative splicing, generating multiple isoforms with divergent transcriptional activities ( Among the best-studied HIF-3 isoforms is inhibitory PAS domain protein (IPAS), which suppresses hypoxia-induced transcription by sequestering HIF-1 and blocking HIF-1/ heterodimer formation ( in vitro and in vivo models confirm that HIF-31 drives liver metastatic colonization, while its suppression reduces metastatic burden ( in vitro and suppresses metastasis in vivo , while restoration of RhoC signaling rescues these phenotypes

K., Gyamerah, E

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