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Cited by 199Iron Metabolism and DisordersTrace Elements in HealthPlant Micronutrient Interactions and Effects

DNA and mRNA elements with complementary responses to hemin, antioxidant inducers, and iron control ferritin-L expression

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Hintze, Korry J., Theil, Elizabeth C.·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0505148102PMC PMC1257710
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Abstract

Ferritins, an ancient family of protein nanocages, concentrate iron in iron–oxy minerals for iron–protein biosynthesis and protection against oxy radical damage. Of the two genetic mechanisms that regulate rates of ferritin-L synthesis, DNA transcription and mRNA translation, more is known about mRNA regulation where iron targets complexes of an mRNA structure, the iron-responsive element (IRE) sequence, and ferritin IRE repressors (iron regulatory proteins 1 and 2). Neither the integration of mRNA and DNA regulation nor the ferritin-L DNA promoter are well studied. We now report the combined effects of DNA transcription and mRNA translation regulation of ferritin-L synthesis. First, the promoter of human ferritin-L, encoding the animal-specific subunit associated with human diseases, was identified, and contained an overlapping Maf recognition element (MARE) and antioxidant responsive element (ARE) that was positively regulated by tert -butylhydroquinone, sulforaphane, and hemin with responses comparable to thioredoxin reductase (ARE regulator) or quinone reductase (MARE/ARE regulator). Iron, a poor regulator of the ferritin-L promoter, was 800 times less effective than sulforaphane. Combining the ferritin-L MARE/ARE and IRE produced a response to hemin that was 3-fold greater than the sum of responses of the MARE/ARE or IRE alone. Regulation of ferritin-L by a MARE/ARE DNA sequence emphasizes the importance of ferritin-L in oxidative stress that complements the mRNA regulation in iron stress. Combining DNA and mRNA mechanisms of regulation, as for ferritin-L, illustrates the advantages of using two types of genetic targets to achieve sensitive responses to multiple signals.

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  • Chemicals used to model PD, such as MPTP, 6-OHDA, and rotenone, increase expression of key members of the signaling pathway associated with the UPR in ER stress.

    “It may be noted that chemicals used to model PD, such as MPTP, 6-hydroxydopamine (6-OHDA), and rotenone, were shown to increase expression of key members of the signaling pathway associated with the UPR in ER stress (136, 327).”

    From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [136]

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Authors
Hintze, K. J., & Theil, E. C.
Affiliations
University of California, Berkeley (US)
Corresponding author
Theil, Elizabeth C.
ORCID
Hintze, Korry J.
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-10-10
Volume
102
Issue
42
Pages
15048-15052
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0505148102
PMC
PMC1257710
OpenAlex
W2127797915
Cited by
199
References
47
Citations by year
2026: 3 · 2025: 19 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 3 · 2020: 9 · 2019: 5 · 2018: 4 · 2017: 9 · 2016: 8 · 2015: 9 · 2014: 14 · 2013: 4 · 2012: 15
FWCI
9.09
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (DK-20251)
  • National Heart, Lung, and Blood Institute (HL 56169, R01HL056169)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 20251, R56DK020251, R01DK020251)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Micronutrient Interactions and Effects
Keywords
iron-responsive element, iron regulatory proteins, antioxidant response element, hemin, sulforaphane, tert-butylhydroquinone, oxidative stress, iron homeostasis, mRNA translation regulation, thioredoxin reductase, quinone reductase
MeSH terms
Animals, Antioxidants, Base Sequence, DNA, Ferritins, Gene Expression Regulation, Hemin, Humans, Iron, Molecular Sequence Data, Promoter Regions, Genetic, RNA, Messenger, Transcription, Genetic, Protein Biosynthesis, Sequence Alignment, Genes, Reporter, Response Elements, Mice

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