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Cited by 213Iron Metabolism and DisordersErythropoietin and Anemia TreatmentNeurological diseases and metabolism

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

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Miller, L L, Miller, S C, Torti, S V, Tsuji, Y, Torti, F M·1991·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.88.11.4946PMC PMC51784
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Abstract

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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Crossref · 10.1073/pnas.88.11.4946

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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)
ORCID
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
DOI
10.1073/pnas.88.11.4946
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
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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