ArticleFree radical biology & medicine2007
The role of ascorbate in the modulation of HIF-1alpha protein and HIF-dependent transcription by chromium(VI) and nickel(II).
Article in Free radical biology & medicine, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 58 citations in OpenAlex.
- Nuclear SUMOylation and Proteotoxic Stress Responses to Metals with Different Ligand Preferences.Chemical research in toxicology · 2025Article
- ATR activation by Cr-DNA damage is a major survival response establishing late S and G2 checkpoints after Cr(VI) exposure.Toxicology and applied pharmacology · 2023Article
- The role of hypoxia-inducible factor 1 alpha (HIF-1α) modulation in heavy metal toxicity.Archives of toxicology · 2023Review
- Renal hypoxia-HIF-PHD-EPO signaling in transition metal nephrotoxicity: friend or foe?Archives of toxicology · 2022Review
- Multifaceted Interplay between Hormones, Growth Factors and Hypoxia in the Tumor Microenvironment.Cancers · 2022Review
- Ascorbate: antioxidant and biochemical activities and their importance for in vitro models.Archives of toxicology · 2021Review
- p62 functions as a signal hub in metal carcinogenesis.Seminars in cancer biology · 2021Review
- NADCell cycle (Georgetown, Tex.) · 2021Article
- 2-Oxoglutarate-dependent dioxygenases in cancer.Nature reviews. Cancer · 2020Review
- Oxidative Stress and Metabolic Reprogramming in Cr(VI) Carcinogenesis.Current opinion in toxicology · 2018Article
- Expression of hypoxia inducible factor 1α and 2α and its association with vitamin C level in thyroid lesions.Journal of biomedical science · 2017Article
- Chemical-agnostic hazard prediction: statistical inference ofComputational toxicology (Amsterdam, Netherlands) · 2017Article
- Vitamin C: the known and the unknown and Goldilocks.Oral diseases · 2016Review
- Restoring physiological levels of ascorbate slows tumor growth and moderates HIF-1 pathway activity in Gulo(-/-) mice.Cancer medicine · 2015Article
- Current limitations of murine models in oncology for ascorbate research.Frontiers in oncology · 2014Review
- Endoplasmic reticulum thiol oxidase deficiency leads to ascorbic acid depletion and noncanonical scurvy in mice.Molecular cell · 2012Article
- Comparative cytotoxicity and genotoxicity of particulate and soluble hexavalent chromium in human and sperm whale (Physeter macrocephalus) skin cells.Comparative biochemistry and physiology. Toxicology & pharmacology : CBP · 2012Article
- Glutathione homeostasis and functions: potential targets for medical interventions.Journal of amino acids · 2012Article
- Effects of ascorbic acid on carcinogenicity and acute toxicity of nickel subsulfide, and on tumor transplants growth in gulonolactone oxidase knock-out mice and wild-type C57BL mice.Toxicology and applied pharmacology · 2011Article
- Vitamins C and E: beneficial effects from a mechanistic perspective.Free radical biology & medicine · 2011Review
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Molecular oxygen is involved in hydroxylation and subsequent degradation of HIF-1alpha, a subunit of HIF-1 transcription factor; therefore oxygen shortage (hypoxia) stabilizes this protein. However, HIF-1alpha can also be stabilized by transition metal ions in the presence of oxygen, suggesting that a different mechanism is involved in metal-induced hypoxic stress. Recently, we showed that the depletion of intracellular ascorbate by metals may lead to the inhibition of hydroxylases. Because nickel(II) has similarity to iron(II), an alternative hypothesis suggests that iron substitution for nickel in the enzyme inhibits hydroxylase activity. Here we investigated the induction of HIF-1 by another metal, chromium, which cannot replace iron in the enzyme. We show that chromium(VI), but not chromium(III), can oxidize ascorbate both in cells and in a cell-free system. In agreement with these data chromium(VI) stabilizes HIF-1alpha protein in cells only until it is reduced to chromium(III). In contrast, nickel(II) was found to be a catalyst, which facilitated continuous oxidation of ascorbate by ambient oxygen. These data correlate with extended stabilization of HIF-1alpha after acute exposure to nickel(II). The HIF-1-dependent reporter assays revealed that 20-24 h was required to fully develop the HIF-1 transcriptional response, and the acute exposure to nickel(II), but not chromium(VI), meets this requirement. However, repeated (chronic) exposure to chromium(VI) can also lead to extended stabilization of HIF-1alpha. Thus, the obtained data emphasize the important role of ascorbate in regulation of HIF-1 transcriptional activity in metal-exposed human lung cells.
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