ArticleThe Journal of biological chemistry2011
Hypoxia-inducible factor α subunit stabilization by NEDD8 conjugation is reactive oxygen species-dependent.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 91 citations in OpenAlex.
- UBE2M deficiency in alveolar macrophages promotes emphysema through HIF-2α/MMP12 axis.Chinese medical journal pulmonary and critical care medicine · 2026Article
- The role of neddylation in colorectal cancer and its therapeutic potential.Discover oncology · 2025Review
- Oxidative stress in cancer: from tumor and microenvironment remodeling to therapeutic frontiers.Molecular cancer · 2025Review
- Low cytoplasmic NUB1 protein exerts hypoxic cell death with poorer prognosis in oestrogen receptor negative breast cancer patients.Translational oncology · 2024Article
- Protein neddylation and its role in health and diseases.Signal transduction and targeted therapy · 2024Review
- Neddylation of insulin receptor substrate acts as a bona fide regulator of insulin signaling and its implications for cancer cell migration.Cancer gene therapy · 2024Article
- Advancements in colorectal cancer research: Unveiling the cellular and molecular mechanisms of neddylation (Review).International journal of oncology · 2024Review
- Review
- Neddylation is required for perinatal cardiac development through stimulation of metabolic maturation.Cell reports · 2023Article
- Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration.American journal of human genetics · 2023Article
- A comprehensive single cell data analysis of lymphoblastoid cells reveals the role of super-enhancers in maintaining EBV latency.Journal of medical virology · 2023Article
- The Next Frontier: Translational Development of Ubiquitination, SUMOylation, and NEDDylation in Cancer.International journal of molecular sciences · 2022Review
- SUMOylation and NEDDylation in Primary and Metastatic Cancers to Bone.Frontiers in cell and developmental biology · 2022Review
- Quantitative analyses for effects of neddylation on CRL2Protein science : a publication of the Protein Society · 2021Article
- Review
- Transcriptomic profile of VEGF-regulated genes in human cervical epithelia.Cell and tissue research · 2021Article
- Neddylation stabilizes Nav1.1 to maintain interneuron excitability and prevent seizures in murine epilepsy models.The Journal of clinical investigation · 2021Article
- Neddylation regulation of mitochondrial structure and functions.Cell & bioscience · 2021Review
- Advances in Cancer Treatment by Targeting the Neddylation Pathway.Frontiers in cell and developmental biology · 2021Review
- The Role of Hypoxia-Inducible Factor Post-Translational Modifications in Regulating Its Localisation, Stability, and Activity.International journal of molecular sciences · 2020Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hypoxia-inducible factor α proteins (HIF-αs) are regulated oxygen dependently and transactivate numerous genes essential for cellular adaptation to hypoxia. NEDD8, a member of the ubiquitin-like family, covalently binds to its substrate proteins, and thus, regulates their stabilities and functions. In the present study, we examined the possibility that the HIF signaling is regulated by the neddylation. HIF-1α expression and activity were inhibited by knocking down APPBP1 E1 enzyme for NEDD8 conjugation but enhanced by ectopically expressing NEDD8. HIF-1α and HIF-2α were identified to be covalently modified by NEDD8. NEDD8 stabilized HIF-1α even in normoxia and further increased its level in hypoxia, which also occurred in von Hippel-Lindau (VHL) protein- or p53-null cell lines. The HIF-1α-stabilizing effect of NEDD8 was diminished by antioxidants and mitochondrial respiratory chain blockers. This suggests that the NEDD8 effect is concerned with reactive oxygen species driven from mitochondria rather than with the prolyl hydroxylase (PHD)/VHL-dependent oxygen-sensing system. Based on these findings, we propose that NEDD8 is an ancillary player to regulate the stability of HIF-1α. Furthermore, given the positive role played by HIF-αs in cancer promotion, the NEDD8 conjugation process could be a potential target for cancer therapy.
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