Regulation of ferrochelatase gene expression by hypoxia
Abstract
Ferrochelatase (FECH), the last enzyme of the heme biosynthetic pathway, catalyzes the insertion of iron into protoporphyrin to form heme. This pathway provides heme for hemoglobin and other essential hemoproteins. The regulatory role of oxygen in the pathway has not been clearly established. In this study, we examined whether FECH gene expression is upregulated during hypoxia by a mechanism which involves the hypoxia-inducible factor 1 (HIF-1). Two HIF-1 binding motifs were identified within the -150 bp FECH minimal promoter sequence. Exposure of HEL, K562, and Hep-G2 cells to hypoxia for 18 hours resulted in a significant increase in FECH mRNA expression (p < 0.05). Hypoxia also transactivated the minimal promoter for the FECH gene in the cells. Transient co-expression of wild-type HIF-1alpha or a dominant negative HIF-1alpha with the FECH minimal promoter luciferase construct stimulated or blocked FECH promoter activity, respectively. Expression of the von Hippel-Lindau (VHL) tumor suppressor factor blocked the expression of both FECH mRNA and HIF-1alpha protein during normoxic culture of renal carcinoma cell line (RCC4). The results suggest that the FECH gene is a target for HIF-1 during hypoxia.
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- Authors
- Liu, Y. L., Ang, S. O., Weigent, D. A., Prchal, J. T., & Bloomer, J. R.
- Affiliations
- University of Alabama at Birmingham (US)
- Baylor College of Medicine (US)
- Corresponding author
- Bloomer, Joseph R.
- Venue
- Life Sciences
- Publisher
- Elsevier BV
- Published
- 2004-09
- Volume
- 75
- Issue
- 17
- Pages
- 2035-2043
- ISSN
- 0024-3205 (ISSN-L)
- OpenAlex
- W2045008450
- Cited by
- 60
- References
- 33
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 4 · 2019: 4 · 2018: 6 · 2017: 5 · 2016: 1 · 2015: 5 · 2013: 6
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Life Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL5007, HL66333, Z01HL005007, R01HL066333)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK26466)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- ferrochelatase, hypoxia, HIF-1, HIF-1α, von Hippel-Lindau tumor suppressor, heme biosynthesis, promoter transactivation, renal carcinoma cells, oxygen regulation
- MeSH terms
- Hypoxia, Base Sequence, Binding Sites, DNA-Binding Proteins, Ferrochelatase, Humans, Luciferases, Molecular Sequence Data, Nuclear Proteins, Promoter Regions, Genetic, RNA, Messenger, Transcription Factors, Transfection, Tumor Cells, Cultured, Blotting, Western, Transcriptional Activation, Gene Expression Regulation, Enzymologic, Genes, Reporter, DNA Primers, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Hypoxia-Inducible Factor 1, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit
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