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Oxygen homeostasis

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Metazoan life is dependent upon the utilization of O2 for essential metabolic processes and oxygen homeostasis is an organizing principle for understanding metazoan evolution, ontology, physiology, and pathology. Hypoxia‐inducible factor 1 (HIF‐1) is a transcription factor that is expressed by all metazoan species and functions as a master regulator of oxygen homeostasis. Recent studies have elucidated complex mechanisms by which HIF‐1 activity is regulated and by which HIF‐1 regulates gene expression, with profound consequences for prenatal development, postnatal physiology, and disease pathogenesis. Copyright © 2009 John Wiley & Sons, Inc.

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Figure 1.

Regulation of HIF‐1 activity. HIF‐1α protein levels and activity are regulated by physiological, pathological, and pharmacological stimuli acting via distinct signal transduction pathways. Regulation by growth factors (lavender arrows): The translation of HIF‐1α mRNA into protein is stimulated by the kinase activity of the mammalian target of rapamycin, which is activated by binding of a growth factor to its cognate RTK and signaling via phosphatidylinositol‐3‐kinase and the serine–threonine kinase AKT. Regulation by O2 concentration: In the presence of O2 (red arrows), prolyl hydroxylase domain protein (PHD)2 hydroxylates HIF‐1α proline residues and a VHL ubiquitin–protein ligase complex binds, leading to ubiquitination (−Ubi) and degradation by the 26S proteasome; O2 also stimulates hydroxylation by FIH‐1 of an asparagine residue in HIF‐1α, which blocks binding of the coactivator protein p300. Under conditions of continuous hypoxia (blue arrows), hydroxylation is inhibited, HIF‐1α dimerizes with HIF‐1α, binds to hypoxia response elements in target genes, and activates transcription via its association with p300. Intermittent hypoxia (green arrows) induces HIF‐1 activity by pathways that ultimately target HIF‐1α synthesis, stability, and transactivation. Modulation by drugs: in cancers treated with an inhibitor of heat shock protein 90 (HSP90), RACK1 binds to HIF‐1α in place of HSP90 and recruits the same ubiquitin ligase complex that is recruited by VHL, but it does so in an O2‐ and PHD2/VHL‐independent manner (orange arrows). Other mechanisms regulating HIF‐1 activity are described in the text.

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Figure 2.

Direct target gene regulation by HIF‐1. (a) HIF‐1 binds to a HRE near a protein‐coding gene (CDS) and recruits coactivators such as p300 to activate transcription. (b) In rare cases, HIF‐1 binding may lead to transcriptional repression, which is likely to involve recruitment of corepressors, possibly in concert with repressors.

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Figure 3.

Indirect regulation of secondary targets by HIF‐1. HIF‐1 directly activates transcription of a gene encoding a transcription factor (CDS‐TF), which binds to a gene containing its TF binding site (TFBS) and either activates (TFA) or represses (TFR) transcription of the respective gene [denoted coding sequence (CDS)‐A and CDS‐B], by recruiting coactivator (CoA) and corepressor (CoR) proteins, respectively.

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Figure 4.

Transcriptional activation of microRNA (miR) clusters by HIF‐1. HIF‐1 binds to an HRE and activates transcription of a primary RNA that is processed to form multiple miRs, each of which binds to multiple mRNAs (for simplicity, each miR is shown binding to only one mRNA) and either blocks mRNA translation or induces mRNA degradation.

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Figure 5.

Epigenetic regulation by HIF‐1. HIF‐1 activates transcription of a gene encoding a histone demethylase (HDM), which modifies chromatin throughout the genome, altering the accessibility of DNA to the transcriptional machinery and thereby regulating the expression of multiple genes.

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Figure 6.

Corepressor function of HIF‐1α. HIF‐1α displaces Myc from binding to the MSH2 gene promoter, thereby repressing transcription of the gene.

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Figure 7.

Coactivator function of HIF‐1α. HIF‐1α binds to the Notch intracellular domain (NICD), which interacts with the DNA‐binding protein CBF‐1 at the Notch response element (NRE) of a Notch target gene (NTG). Recruitment of HIF‐1α augments NICD‐dependent transactivation of the NTG.

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Figure 8.

Regulation of erythropoiesis. In the kidney, hypoxia induces the synthesis of erythropoietin (EPO), which is secreted into the bloodstream. The binding of EPO to EPO receptors located on bone marrow erythroid progenitor cells stimulates their survival, proliferation, and differentiation. Iron is required for the synthesis of hemoglobin by erythroid progenitors. Intestinal iron absorption is controlled by the divalent metal transporter 1 (DMT1), which is induced by hypoxia in a HIF‐2α‐dependent manner. In the liver, hypoxia represses hepcidin production, leading to increased levels of ferroportin, which is required for the mobilization of iron from macrophages that have ingested aged red cells and for the absorption of iron from the intestine. Iron is transported through the blood by transferrin and taken up by erythroid progenitor cells via the transferrin receptor. HIF‐1α and HIF‐2α control erythropoiesis by coordinately regulating the expression of EPO, EPO receptor, transferrin, transferrin receptor, hepcidin, and DMT1.

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Figure 9.

Pathogenesis of hypoxic pulmonary hypertension. Alveolar hypoxia induces increased HIF‐1 activity leading to transcriptional repression of genes encoding voltage‐gated potassium channels (Kv 1.5 and Kv 2.1) and transcriptional activation of genes encoding channels (TRPC1 and TRPC6), the sodium–hydrogen exchanger 1 (NHE1), and endothelin 1 (EDN1) that alter the intracellular concentrations of potassium [(K+)i], calcium [(Ca2+)i], and hydrogen [(H+)i] ions, leading to smooth muscle cell contraction and proliferation [as well as hypertrophy (not shown)] and consequent reduced luminal diameter of pulmonary arterioles.

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