Oxygen sensing and signaling: impact on the regulation of physiologically important genes.
A growing number of physiologically relevant genes are regulated in response to changes in intracellular oxygen tension. It is likely that cells from a wide variety of tissues share a common mechanism of oxygen sensing and signal transduction leading to the activation of the transcription factor hypoxia-inducible factor 1 (HIF-1). Besides hypoxia, transition metals (Co2+, Ni2+ and Mn2+) and iron chelation also promote activation of HIF-1. Induction of HIF-1 by hypoxia is blocked by the heme ligands carbon monoxide and nitric oxide. There is growing, albeit indirect, evidence that the oxygen sensor is a flavoheme protein and that the signal transduction pathway involves changes in the level of intracellular reactive oxygen intermediates. The activation of HIF-1 by hypoxia depends upon signaling-dependent rescue of its alpha-subunit from oxygen-dependent degradation in the proteasome, allowing it to form a heterodimer with HIF-1beta (ARNT), which then translocates to the nucleus and impacts on the transcription of genes whose cis-acting elements contain cognate hypoxia response elements.
Zhu
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Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Bunn
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HF
D000818:Animals; D002344:Carotid Body / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004921:Erythropoietin / Q000096:biosynthesis; D005786:Gene Expression Regulation; D006420:Hemeproteins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D000860:Hypoxia / Q000235:genetics / Q000503:physiopathology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D066298:In Vitro Techniques; D008954:Models, Biological; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D006420:Hemeproteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D004921:Erythropoietin; D006861:Hydrogen Peroxide; D009247:NADH, NADPH Oxidoreductases; D010100:Oxygen