The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
Iron-independent induction of ferritin H chain by tumor necrosis factor
Open accessAbstract
Iron increases the synthesis of the iron-storage protein, ferritin, largely by promoting translation of preexisting mRNAs for both the H and L ferritin isoforms (H, heavy, heart, acidic; L, light, liver, basic). We have recently cloned and sequenced a full-length cDNA to murine ferritin H and identified ferritin H as a gene induced by tumor necrosis factor alpha (TNF-alpha, cachectin). Using primary human myoblasts, we have now examined the relationship between TNF-alpha and iron in regulating ferritin. Four lines of evidence suggest that TNF-alpha regulates ferritin independently of iron. First, evaluation of mRNA showed that TNF-alpha increased ferritin H chain specifically, provoking no change in steady-state levels of ferritin L mRNA; iron, in contrast, increased the mRNA of both isoforms. Second, the increase in ferritin H protein synthesis observed during TNF-alpha treatment was dependent on an increase in ferritin H mRNA: actinomycin D blocked the TNF-alpha-induced changes in ferritin H but did not inhibit the translational induction of ferritin seen with iron treatment. Third, equal ferritin mRNA induction was observed in iron-loaded cells and in cells depleted of iron by a permeant chelator, 2,2'-dipyridyl. Fourth, ferritin H induction by TNF-alpha and iron was additive over the entire range of iron concentrations, even at TNF-alpha doses known to maximally stimulate ferritin H mRNA levels. Nonetheless, the role of iron in translational regulation of ferritin was retained in TNF-alpha-treated cells; effective biosynthesis of TNF-alpha-induced, H-subunit-predominant ferritin protein required iron and could be enhanced by treatment of the cells with additional iron or blocked by 2,2'-dipyridyl. Finally, we observed that the TNF-alpha-mediated increase in ferritin synthesis peaked at 8 hr and was followed by a decrease in both H and L isoferritin synthesis; the addition of iron, however, reversed the late-occurring depression in ferritin synthesis. This suggests that TNF-alpha-induced synthesis of H-rich ferritin may reduce the regulatory pool of intracellular iron, secondarily inhibiting iron-mediated translation of ferritin mRNA. We conclude that TNF-alpha acts independently of iron in its induction of ferritin H mRNA but requires the presence of iron for this effect to be fully expressed at the protein level.
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Fluorescence analysis of the labile iron pool of mammalian cells
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Metadata
- Authors
- Miller, L. L., Miller, S. C., Torti, S. V., Tsuji, Y., & Torti, F. M.
- Affiliations
- Stanford Medicine (US)
- SRI International (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1991-06
- Volume
- 88
- Issue
- 11
- Pages
- 4946-4950
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC51784
- OpenAlex
- W2016762244
- Cited by
- 213
- References
- 38
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 2 · 2023: 4 · 2022: 6 · 2021: 4 · 2020: 4 · 2019: 7 · 2018: 7 · 2017: 1 · 2016: 3 · 2015: 7 · 2014: 4 · 2013: 7 · 2012: 2
- FWCI
- 4.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-42412)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- TNF-α, translational regulation, iron storage, myoblasts, 2,2'-bipyridine, iron chelation, actinomycin D, protein synthesis
- MeSH terms
- Cells, Cultured, Dactinomycin, Ferritins, Humans, Iron, Kinetics, Muscles, Recombinant Proteins, RNA, Messenger, Protein Biosynthesis, Tumor Necrosis Factor-alpha, 2,2'-Dipyridyl, Macromolecular Substances
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