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Role of Hypoxia-inducible Factor-1 in Transcriptional Activation of Ceruloplasmin by Iron Deficiency
Open accessAbstract
A role of the copper protein ceruloplasmin (Cp) in iron metabolism is suggested by its ferroxidase activity and by the tissue iron overload in hereditary Cp deficiency patients. In addition, plasma Cp increases markedly in several conditions of anemia, e.g. iron deficiency, hemorrhage, renal failure, sickle cell disease, pregnancy, and inflammation. However, little is known about the cellular and molecular mechanism(s) involved. We have reported that iron chelators increase Cp mRNA expression and protein synthesis in human hepatocarcinoma HepG2 cells. Furthermore, we have shown that the increase in Cp mRNA is due to increased rate of transcription. We here report the results of new studies designed to elucidate the molecular mechanism underlying transcriptional activation of Cp by iron deficiency. The 5'-flanking region of the Cp gene was cloned from a human genomic library. A 4774-base pair segment of the Cp promoter/enhancer driving a luciferase reporter was transfected into HepG2 or Hep3B cells. Iron deficiency or hypoxia increased luciferase activity by 5-10-fold compared with untreated cells. Examination of the sequence showed three pairs of consensus hypoxia-responsive elements (HREs). Deletion and mutation analysis showed that a single HRE was necessary and sufficient for gene activation. The involvement of hypoxia-inducible factor-1 (HIF-1) was shown by gel-shift and supershift experiments that showed HIF-1alpha and HIF-1beta binding to a radiolabeled oligonucleotide containing the Cp promoter HRE. Furthermore, iron deficiency (and hypoxia) did not activate Cp gene expression in Hepa c4 hepatoma cells deficient in HIF-1beta, as shown functionally by the inactivity of a transfected Cp promoter-luciferase construct and by the failure of HIF-1 to bind the Cp HRE in nuclear extracts from these cells. These results are consistent with in vivo findings that iron deficiency increases plasma Cp and provides a molecular mechanism that may help to understand these observations.
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Metadata
- Authors
- Mukhopadhyay, C. K., Mazumder, B., & Fox, P. L.
- Affiliations
- Cleveland Clinic (US)
- Corresponding author
- Fox, Paul L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-07
- Volume
- 275
- Issue
- 28
- Pages
- 21048-21054
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2030992731
- Cited by
- 274
- References
- 68
- Citations by year
- 2025: 2 · 2024: 7 · 2023: 12 · 2022: 7 · 2021: 11 · 2020: 11 · 2019: 6 · 2018: 9 · 2017: 3 · 2016: 10 · 2015: 7 · 2014: 10 · 2013: 16 · 2012: 13
- FWCI
- 8.15
- 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 29582, P01HL029582)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Keywords
- ceruloplasmin, HIF-1, iron deficiency, transcriptional activation, hypoxia response element, HIF-1α, ARNT, iron metabolism, anemia, HepG2 cells, iron chelators
- MeSH terms
- Anemia, Animals, Base Sequence, Ceruloplasmin, Cloning, Molecular, DNA-Binding Proteins, Enhancer Elements, Genetic, Erythropoietin, Female, Gene Expression Regulation, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Molecular Sequence Data, Nuclear Proteins, Pregnancy, Promoter Regions, Genetic, Recombinant Proteins, Transcription Factors, Transfection, Tumor Cells, Cultured, Transcriptional Activation, Consensus Sequence, Sequence Alignment, Anemia, Iron-Deficiency, Mice, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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