ArticleThe Journal of biological chemistry2014
Tight control of hypoxia-inducible factor-α transient dynamics is essential for cell survival in hypoxia.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 72 citations in OpenAlex.
- Article
- A Mechanistic Model of the HIF-1/HIF-2 Switch Regulating Hypoxia-Induced Cancer Stemness.International journal of molecular sciences · 2026Article
- A Split sfGFP-Based Signal-Amplified Reporter System for Enhanced Detection of Promoter Activity.Biotechnology journal · 2026Article
- Revealing erythropoietin variant EV-3 as novel driving force and immunotherapeutic target in human glioblastoma.Journal of experimental & clinical cancer research : CR · 2025Article
- Progressive Deactivation of Hydroxylases Controls Hypoxia-Inducible Factor-1α-Coordinated Cellular Adaptation to Graded Hypoxia.Research (Washington, D.C.) · 2025Article
- Oscillatory hypoxia induced gene expression predicts low survival in human breast cancer patients.Molecular carcinogenesis · 2024Article
- Hypoxic-Normoxic Crosstalk Activates Pro-Inflammatory Signaling in Human Cardiac Fibroblasts and Myocytes in a Post-Infarct Myocardium on a Chip.Advanced healthcare materials · 2024Article
- Foxp1 suppresses cortical angiogenesis and attenuates HIF-1alpha signaling to promote neural progenitor cell maintenance.EMBO reports · 2024Article
- Tissue-of-origin for cancers determines HIF-1 activation induced phenotypic heterogeneity.Molecular carcinogenesis · 2024Article
- An optimized reporter of the transcription factor hypoxia-inducible factor 1α reveals complex HIF-1α activation dynamics in single cells.The Journal of biological chemistry · 2023Article
- Lactate-dependent chaperone-mediated autophagy induces oscillatory HIF-1α activity promoting proliferation of hypoxic cells.Cell systems · 2022Article
- A novel mechanism for inhibiting proliferation of rheumatoid arthritis fibroblast-like synoviocytes: geniposide suppresses HIF-1α accumulation in the hypoxic microenvironment of synovium.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2022Article
- Elucidating the role of hypoxia-inducible factor in rheumatoid arthritis.Inflammopharmacology · 2022Review
- Article
- Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy.Cancers · 2022Review
- Hypoxia-induced HIF1α activation regulates small extracellular vesicle release in human embryonic kidney cells.Scientific reports · 2022Article
- Oxygen-sensing mechanisms in development and tissue repair.Development (Cambridge, England) · 2021Review
- STAT3 governs the HIF-1α response in IL-15 primed human NK cells.Scientific reports · 2021Article
- Angiogenesis: A Cellular Response to Traumatic Injury.Shock (Augusta, Ga.) · 2021Review
- Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Intracellular signaling involving hypoxia-inducible factor (HIF) controls the adaptive responses to hypoxia. There is a growing body of evidence demonstrating that intracellular signals encode temporal information. Thus, the dynamics of protein levels, as well as protein quantity and/or localization, impacts on cell fate. We hypothesized that such temporal encoding has a role in HIF signaling and cell fate decisions triggered by hypoxic conditions. Using live cell imaging in a controlled oxygen environment, we observed transient 3-h pulses of HIF-1α and -2α expression under continuous hypoxia. We postulated that the well described prolyl hydroxylase (PHD) oxygen sensors and HIF negative feedback regulators could be the origin of the pulsatile HIF dynamics. We used iterative mathematical modeling and experimental analysis to scrutinize which parameter of the PHD feedback could control HIF timing and we probed for the functional redundancy between the three main PHD proteins. We identified PHD2 as the main PHD responsible for HIF peak duration. We then demonstrated that this has important consequences, because the transient nature of the HIF pulse prevents cell death by avoiding transcription of p53-dependent pro-apoptotic genes. We have further shown the importance of considering HIF dynamics for coupling mathematical models by using a described HIF-p53 mathematical model. Our results indicate that the tight control of HIF transient dynamics has important functional consequences on the cross-talk with key signaling pathways controlling cell survival, which is likely to impact on HIF targeting strategies for hypoxia-associated diseases such as tumor progression and ischemia.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.