The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.
Modulation of hypoxia-inducible factor-1 alpha in cultured primary cells by intracellular ascorbate
Abstract
Control of the transcription factor hypoxia inducible factor (HIF)-1 is mediated by hydroxylation by proline and asparagine hydroxylases. These enzymes require ascorbate for optimal activity, but little attention has been given to the effect of ascorbate on HIF-1 activation. Furthermore, cells in culture are ascorbate deficient. We investigated the effect of intracellular ascorbate on HIF-1alpha protein levels and on HIF-1-mediated gene expression in two human primary cell lines (umbilical vein endothelial cells and skin fibroblasts) and one human cancer cell line (A431 epithelial cells). Under normal culture conditions the cells contained no ascorbate and adding ascorbate to the medium increased intracellular concentrations in a dose-dependent manner. A basal level of HIF-1alpha detected in nonsupplemented cells under normoxic conditions disappeared when 10 microM ascorbate was added to the medium. Induction of HIF-1alpha by hypoxia (1% O(2)) or by CoCl(2) was markedly inhibited by ascorbate and loading with physiological levels resulted in almost complete reversal of HIF-1alpha stabilisation. Gene expression was similarly affected, with VEGF mRNA and GLUT-1 up-regulation being inhibited by ascorbate. Hence intracellular ascorbate is a major regulator of the hypoxic response in normal cells and optimal levels of this vitamin will have a profound effect on HIF-1-regulated processes.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Through the stimulation of regulatory hydroxylases, vitamin C also regulates the stabilization and activation of the hypoxia-inducible factor (HIF)-1, a metabolic sensor that controls the expression of hundreds of genes involved with cell survival and tissue remodelling, including collagenases [103,104,105].”
From The Roles of Vitamin C in Skin Health. (2017) · cites this paper as [103]
Citations
Cites
Jaffe, E. A., Nachman, R., Becker, C. G., & Minick, C. (1973) · Journal of Clinical Investigation · doi:10.1172/jci107470 · Cited by 7,146
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717
Oxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068
Lando, D., Peet, D. J., Gorman, J. J., Whelan, D. A., Whitelaw, M. L., & Bruick, R. K. (2002) · Genes & Development · doi:10.1101/gad.991402 · Cited by 1,550
Wenger, R. H. (2002) · The FASEB Journal · doi:10.1096/fj.01-0944rev · Cited by 1,135
Maxwell, P. H., Dachs, G. U., Gleadle, J. M., Nicholls, L. G., Harris, A. L., Stratford, I. J., Hankinson, O., Pugh, C. W., & Ratcliffe, P. J. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.15.8104 · Cited by 1,084
Self-citationCharacterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor
Hirsilä, M., Koivunen, P., Günzler, V., Kivirikko, K. I., & Myllyharju, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304982200 · Cited by 794
Oxidative DNA damage and senescence of human diploid fibroblast cells.
Chen, Q., Fischer, A., Reagan, J. D., Yan, L. J., & Ames, B. N. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.10.4337 · Cited by 720
New Concepts in the Biology and Biochemistry of Ascorbic Acid
Flier, J. S., Underhill, L. H., & Levine, M. (1986) · New England Journal of Medicine · doi:10.1056/nejm198604033141407 · Cited by 646
Proline hydroxylation and gene expression
Kaelin, W. G. (2005) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.74.082803.133142 · Cited by 468
Flagged first, then by citations
Cited by
Sorted by citations
Ascorbic acid: Chemistry, biology and the treatment of cancer
Du, J., Cullen, J. J., & Buettner, G. R. (2012) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2012.06.003 · Cited by 1,106
Vitamin C: The known and the unknown and Goldilocks
Padayatty, S., & Levine, M. (2016) · Oral Diseases · doi:10.1111/odi.12446 · Cited by 753
The Roles of Vitamin C in Skin Health.
Pullar, J., Carr, A., & Vissers, M. (2017) · Nutrients · doi:10.3390/nu9080866 · Cited by 756
Self-citationNew developments and novel therapeutic perspectives for vitamin C
Li, Y., & Schellhorn, H. E. (2007) · The Journal of Nutrition · doi:10.1093/jn/137.10.2171 · Cited by 508
Role of Vitamin C in the Function of the Vascular Endothelium
May, J. M., & Harrison, F. E. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2013.5205 · Cited by 358
Metadata
- Authors
- Vissers, M. C. M., Gunningham, S. P., Morrison, M. J., Dachs, G. U., & Currie, M. J.
- Corresponding author
- Vissers, Margret C.M.
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2007-03
- Volume
- 42
- Issue
- 6
- Pages
- 765-772
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W1984689645
- Cited by
- 125
- References
- 56
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 9 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 5 · 2019: 9 · 2018: 4 · 2017: 7 · 2016: 8 · 2015: 5 · 2014: 15 · 2013: 8 · 2012: 7
- FWCI
- 1.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Chinese Academy of Agricultural Sciences
- Health Research Council of New Zealand
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- hypoxia-inducible factor-1α, vitamin C, prolyl hydroxylase, asparaginyl hydroxylase, HIF-1α stabilization, hypoxia response, vascular endothelial growth factor, GLUT1, umbilical vein endothelial cells, dermal fibroblasts, cobalt chloride, normoxia
- MeSH terms
- Hypoxia, Ascorbic Acid, Cells, Cultured, Dose-Response Relationship, Drug, Endothelium, Vascular, Fibroblasts, Gene Expression Regulation, Humans, RNA, Messenger, Blotting, Western, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Glucose Transporter Type 1, Hypoxia-Inducible Factor 1, alpha Subunit
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
