ArticleCellular & molecular biology letters2022
The transition from HIF-1 to HIF-2 during prolonged hypoxia results from reactivation of PHDs and HIF1A mRNA instability.
Article in Cellular & molecular biology letters, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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86 citing papers in PubMed, 116 citations in OpenAlex.
- Identification of novel HIF2α inhibitors: a structure-based virtual screening approach.Journal of enzyme inhibition and medicinal chemistry · 2026Article
- Hepatic HIF2α Modulates Extra-Hepatic Disease-Associated Phenotypes During Metabolic Dysfunction-Associated Steatotic Liver Disease.Comprehensive physiology · 2026Article
- Elucidating the coordination of mitochondrial maintenance, functional preservation and glycolytic metabolism in HFood chemistry: X · 2026Article
- A plasma derived hypoxia signature predicts benefit from hypoxia-modifying radiotherapy and reveals dynamic humoral immune modulation in bladder cancer.British journal of cancer · 2026Article
- A multilayered stress-response circuit: The mammalian mitochondrial UPR.The FEBS journal · 2026Review
- Diagnostic accuracy and smoking-driven modulation of salivary MMP-8, MMP-9, and HIF-1α in stage III grade B/C periodontitis: a cross-sectional study.Clinical oral investigations · 2026Article
- The developing tendon and enthesis are hypoxic and rely on hypoxia-inducible factor 1a during postnatal development.Development (Cambridge, England) · 2026Article
- HIF inhibition: Current strategies and clinical challenges.Redox biology · 2026Review
- Article
- Intermittent Hypoxia Maintains Neovascular Blood-Brain Barrier Integrity Via the HIF-1α/VEGFB Axis.Translational stroke research · 2026Article
- A Mechanistic Model of the HIF-1/HIF-2 Switch Regulating Hypoxia-Induced Cancer Stemness.International journal of molecular sciences · 2026Article
- Association of Obstructive Sleep Apnea Risk with Hypoxia-Inducible Factor Expression in Chronic Rhinosinusitis by Inflammatory Endotype.Journal of clinical medicine · 2026Article
- Hypoxia Independently Induces AID Expression in CH12 B Cells.European journal of immunology · 2026Article
- Engineered atopic dermatitis models for recreating hypoxic conditions in atopic dermatitis microenvironments.Bioactive materials · 2026Article
- Impeding hypoxia-driven tumor progression in hepatocellular carcinoma: clinical and pre-clinical analyses using 2D and 3D in vitro models.Biology direct · 2026Article
- DNA topological regulation by topoisomerase IIβ-DNA-PK interaction is important for controlled hypoxia-inducible gene expression.bioRxiv : the preprint server for biology · 2026Article
- Lung Vascular Remodeling and Oxidative Damage Induced by Chronic Intermittent Hypoxia.International journal of molecular sciences · 2026Article
- Changes in the Expression Levels of Hypoxia-Inducible Factor Isoforms and Their Regulating microRNAs in Peripheral Blood Leukocytes after Hypoxic Exposure in Wistar Rats with Different Tolerance to Oxygen Deficiency.Bulletin of experimental biology and medicine · 2026Article
- Cell-free mitochondrial DNA as a potential predictor for hypoxic stress.Molecular biology reports · 2026Article
- Understanding Immune Cell Adaptation to Tumor Hypoxia for Maximized Therapeutic Efficacy of Immunotherapy: Biology and Non-invasive Imaging Application.Cancer research and treatment · 2026Review
26 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
The hypoxia-inducible factors (HIF) are transcription factors that activate the adaptive hypoxic response when oxygen levels are low. The HIF transcriptional program increases oxygen delivery by inducing angiogenesis and by promoting metabolic reprograming that favors glycolysis. The two major HIFs, HIF-1 and HIF-2, mediate this response during prolonged hypoxia in an overlapping and sequential fashion that is referred to as the HIF switch. Both HIF proteins consist of an unstable alpha chain and a stable beta chain. The instability of the alpha chains is mediated by prolyl hydroxylase (PHD) activity during normoxic conditions, which leads to ubiquitination and proteasomal degradation of the alpha chains. During normoxic conditions, very little HIF-1 or HIF-2 alpha-beta dimers are present because of PHD activity. During hypoxia, however, PHD activity is suppressed, and HIF dimers are stable. Here we demonstrate that HIF-1 expression is maximal after 4 h of hypoxia in primary endothelial cells and then is dramatically reduced by 8 h. In contrast, HIF-2 is maximal at 8 h and remains elevated up to 24 h. There are differences in the HIF-1 and HIF-2 transcriptional profiles, and therefore understanding how the transition between them occurs is important and not clearly understood. Here we demonstrate that the HIF-1 to HIF-2 transition during prolonged hypoxia is mediated by two mechanisms: (1) the HIF-1 driven increase in the glycolytic pathways that reactivates PHD activity and (2) the much less stable mRNA levels of HIF-1α (HIF1A) compared to HIF-2α (EPAS1) mRNA. We also demonstrate that the alpha mRNA levels directly correlate to the relative alpha protein levels, and therefore to the more stable HIF-2 expression during prolonged hypoxia.
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