HIF1α Signaling

Hypoxia-Inducible Factor (HIF1) is a basic helix-loop-helix transcription factor that transactivates genes encoding proteins that participate in homeostatic responses to hypoxia. It induces expression of proteins controlling glucose metabolism, cell proliferation, and angiogenesis. Several genes involved in cellular differentiation are directly or indirectly regulated by hypoxia. These include Epo, lactate dehydrogenase A (LDHA), ET1, transferrin, transferrin receptor, VEGF, PDGF-β, FGF, and genes affecting glycolysis.HIF1 is a heterodimer of two basic helix-loop-helix PAS (Per-ARNT-Sim) proteins, HIF1-α and HIF1-β. HIF1-α accumulates under hypoxic conditions whereas HIF1-β is constitutively expressed. HIF1-α is an important mediator of the hypoxic response of tumor cells and controls the upregulation of a number of factors important for solid tumor expansion including the angiogenic factor VEGF. HIF1-β is also known as the aryl hydrocarbon receptor nuclear Translocator (ARNT), an essential component of the xenobiotic response.In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing pVHL. Human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Prolyl hydroxylase (PHD1/2) post-translationally modifies HIF1-α, allowing it to interact with the VHL complex. All prolyl hydroxylase isoforms can hydroxylate HIF1-α. In the presence of oxygen, EGLN proteins are active and hydroxylate the ODD domain of HIF1-α, which allows pVHL to bind and polyubiquitinate HIF. VHL is part of a larger complex that includes Elongin-B, Elongin-C, Cul2, RBX1 and an ubiquitin-conjugating enzyme (E2). This complex, together with a ubiquitin-activating enzyme (E1), mediates the Ubiquitylation of HIF1-α. The Ubiquitination targets HIF1-α for degradation, which can be blocked by proteasome inhibitors. Under hypoxic conditions, HIF1-α subunits are not recognized by pVHL, and they consequently accumulate and dimerize with HIF1-β and translocate to the nucleus, where they interact with cofactors such as CBP/p300 and the Pol II complex to bind to HREs and activate transcription of target genes. HIF1-α-activated genes include VEGF, which promotes angiogenesis; GLUT1, which activates glucose transport; LDHA, which is involved in the glycolytic pathway; and Epo, which induces erythropoiesis. HIF1-α also activates transcription of NOS, which promotes vasodilation and angiogenesis. HIF1-α can also be regulated by MAPK and Akt via phosphorylation. MAPKs are in turn activated by the Ras-Raf-MEK cascade. Growth factor bound RTKs activate Ras by binding to SHC, GRB2 and SOS. RTKs also activate PI3K which further activates Akt to regulate HIF1α activity. HIF1-α also associates with the molecular chaperone HSP90. HSP90 antagonists inhibit HIF1-α transcriptional activity and dramatically reduce both hypoxia-induced accumulation of VEGF mRNA and hypoxia-dependent angiogenic activity.Hypoxia also induces p53 protein accumulation. p53 directly interacts with HIF1-α and limits hypoxia-induced expression of HIF1-α by promoting MDM2-mediated ubiquitination and proteasomal degradation of HIF1α. Furthermore, the degradation of HIF1-α by p53 under hypoxic conditions is inhibited by direct interaction with JAB1, which blocks the interaction of HIF1α and p53. HIF1-α also associates with HNF4α2), which activates the Epo gene in concert with HIF1α in response to hypoxic conditions. Hypoxia contributes significantly to the pathophysiology of major categories of human disease, including myocardial and cerebral ischemia, cancer, pulmonary hypertension, congenital heart disease and chronic obstructive pulmonary diseases. (Upgraded 03/2020)