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Pathway Description
HIF-1 (Hypoxia) Signaling
Homo sapiens
Signaling Pathway
Created: 2025-03-16
Last Updated: 2025-04-21
Hypoxia triggers stabilization of hypoxia‑inducible factors (HIFs), oxygen‑sensitive transcription factors that orchestrate adaptive responses by inducing genes involved in angiogenesis, erythropoiesis, metabolism, and survival. Under normal oxygen (normoxia), HIF‑1α is prolyl‑hydroxylated by PHD1–3 and asparaginyl‑hydroxylated by FIH, leading to von Hippel–Lindau (pVHL) E3 ligase recognition and proteasomal degradation. During hypoxia, PHDs and FIH are inactive, allowing HIF‑1α to accumulate, dimerize with HIF‑1β/ARNT, recruit CBP/p300 coactivators, and bind hypoxia response elements (HREs) in target promoters, activating transcription of over 100 genes. Growth factors such as insulin feed into PI3K–AKT–mTORC1. Active mTORC1 phosphorylates S6K1 and 4E‑BP1, enhancing translation initiation—including that of HIF‑1α mRNA—and thereby increasing HIF‑1α protein levels, even under hypoxia; MAPK–ERK boosts HIF‑1α stability and co‑activator recruitment; mitochondrial reactive oxygen species (ROS) inhibit PHDs; and pro‑inflammatory cytokines (e.g., TNF‑α, IL‑1β) enhance HIF‑1α transcription through NF‑κB. Key HIF targets include vascular endothelial growth factor (VEGF) for angiogenesis, erythropoietin (EPO) for red blood cell production, glucose transporters (GLUT1/3) and glycolytic enzymes (e.g., HK2, LDHA) for metabolic reprogramming, and matrix metalloproteinases (MMPs) and chemokine receptors (e.g., CXCR4) for cell migration and invasion.
References
HIF-1 (Hypoxia) Signaling References
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