Hypoxia Alters Iron-regulatory Protein-1 Binding Capacity and Modulates Cellular Iron Homeostasis in Human Hepatoma and Erythroleukemia Cells
Open accessAbstract
Ferritin and transferrin receptor expression is post-transcriptionally regulated by a conserved mRNA sequence termed the iron-responsive element (IRE), to which a transacting protein called the iron-regulatory protein (IRP) is bound. Our data demonstrate that hypoxia powerfully enhances IRE/IRP-1 binding in human cell lines. Using the human hepatoma cell line Hep3B as a model, we found that 16 h in a 1% oxygen atmosphere markedly increases IRE/IRP-1 binding as assessed by electromobility shift assay. Hypoxia also decreased cytosolic aconitase activity. The hypoxia-enhanced IRE/IRP-1 binding stabilized the transferrin receptor message, increased the cellular mRNA content by over 10-fold, and doubled surface receptor expression. Simultaneously, hypoxia suppressed ferritin message translation. Hypoxia's effect was most strikingly depicted by the absence of ferritin synthesis in cells challenged with inorganic iron. Our results contrast with previously reported data (Hanson, E. S., and Leibold, E. A. (1998) J. Biol. Chem. 273, 7588-7593) in which a 3% oxygen atmosphere reduced IRE/IRP-1 binding in rat hepatoma cells. We discuss some possible reasons for the differences. In aggregate with other investigations involving responses to hypoxia, iron, or nitric oxide, our data indicate that cellular iron metabolic responses are complex and that IRE/IRP-1 interactions vary between cell lines and perhaps between species.
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BMP9, BMP4, and BMP2 are inducers of hepcidin.
“More recently, BMP9, BMP4, and BMP2 were identified as inducers of hepcidin (300).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [300]
Induction of hepcidin by exogenous BMPs was greater than that caused by LPS.
“Induction by administration of exogenous BMPs was greater than that caused by treatment with LPS (300).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [300]
BMP-mediated induction of hepcidin was similar in wild-type congenic strains, IL-6 knockout, HFE knockout, and TfR2 mutant mice.
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From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [300]
BMP-mediated activation of hepcidin expression may not require IL-6, HFE, or TfR2.
“suggesting that BMP-mediated activation of hepcidin expression may not require these proteins (300).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [300]
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- Authors
- Toth, I., Yuan, L., Rogers, J. T., Boyce, H., & Bridges, K. R.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Bridges, Kenneth R.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-02
- Volume
- 274
- Issue
- 7
- Pages
- 4467-4473
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2095571987
- Cited by
- 91
- References
- 43
- Citations by year
- 2025: 2 · 2022: 1 · 2020: 1 · 2019: 4 · 2018: 1 · 2016: 1 · 2015: 5 · 2014: 4 · 2013: 3 · 2012: 1
- FWCI
- 4.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 457940)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- hypoxia, iron regulatory protein 1, iron-responsive element, cellular iron homeostasis, transferrin receptor, ferritin, aconitase, mRNA stability, post-transcriptional regulation, hepatoma cells, erythroleukemia cells
- MeSH terms
- Animals, DNA, Leukemia, Erythroblastic, Acute, Ferritins, Carcinoma, Hepatocellular, Homeostasis, Humans, Iron, Iron-Sulfur Proteins, Liver Neoplasms, Oxygen, Protein Binding, Receptors, Transferrin, RNA, Messenger, Surface Properties, Tumor Cells, Cultured, RNA-Binding Proteins, Iron-Regulatory Proteins, Rats
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