Cited by 551Iron Metabolism and DisordersRNA and protein synthesis mechanismsRNA Research and Splicing

An iron-responsive element type II in the 5'-untranslated region of the Alzheimer's amyloid precursor protein transcript

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Rogers, Jack T., Randall, Jeffrey D., Cahill, Catherine M., Eder, Paul S., Huang, Xudong, Gunshin, Hiromi, Leiter, Lorene, McPhee, Jay +8 more·2002·Journal of Biological Chemistry

Abstract

Iron-responsive elements (IREs) are the RNA stem loops that control cellular iron homeostasis by regulating ferritin translation and transferrin receptor mRNA stability. We mapped a novel iron-responsive element (IRE-Type II) within the 5'-untranslated region (5'-UTR) of the Alzheimer's amyloid precursor protein (APP) transcript (+51 to +94 from the 5'-cap site). The APP mRNA IRE is located immediately upstream of an interleukin-1 responsive acute box domain (+101 to +146). APP 5'-UTR conferred translation was selectively down-regulated in response to intracellular iron chelation using three separate reporter assays (chloramphenicol acetyltransferase, luciferase, and red fluorescent protein reflecting an inhibition of APP holoprotein translation in response to iron chelation. Iron influx reversed this inhibition. As an internal control to ensure specificity, a viral internal ribosome entry sequence was unresponsive to intracellular iron chelation with desferrioxamine. Using RNA mobility shift assays, the APP 5'-UTRs, encompassing the IRE, bind specifically to recombinant iron-regulatory proteins (IRP) and to IRP from neuroblastoma cell lysates. IRP binding to the APP 5'-UTR is reduced after treatment of cells with desferrioxamine and increased after interleukin-1 stimulation. IRP binding is abrogated when APP cRNA probe is mutated in the core IRE domain (Delta4 bases:Delta83AGAG86). Iron regulation of APP mRNA through the APP 5'-UTR points to a role for iron in the metabolism of APP and confirms that this RNA structure can be a target for the selection of small molecule drugs, such as desferrioxamine (Fe chelator) and clioquinol (Fe, Cu, and Zn chelator), which reduce Abeta peptide burden during Alzheimer's disease.

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Crossref · 10.1074/jbc.m207435200

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  • Increases in interleukin-1 production increase IRP binding to APP 5'-untranslated region, thereby decreasing APP production.

    “Conversely, increases in interleukin-1 production, increase IRP binding to APP 5’-untranslated region, thereby decreasing APP production.81”
  • Iron might modulate APP processing through the interaction of IRPs with a putative IRE in the 5'-untranslated region of its mRNA.

    “Iron might modulate APP processing through the interaction of IRPs with a putative IRE in the 5’-untranslated region of its mRNA, located immediately upstream of an interleukin-1 responsive acute box domain.81”
  • IRP binding to IRE might interfere with APP translation and translocation across the endoplasmic reticulum membrane; the interference could be substantial because α secretase activity needs membrane-bound APP.

    “IRP binding to IRE might interfere with APP translation and translocation across the endoplasmic reticulum membrane; the interference could be substantial because α secretase activity needs membrane-bound APP.81”

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Authors
Rogers, J. T., Randall, J. D., Cahill, C. M., Eder, P. S., Huang, X., Gunshin, H., Leiter, L., McPhee, J., Sarang, S. S., Utsuki, T., Greig, N. H., Lahiri, D. K., Tanzi, R. E., Bush, A. I., Giordano, T., & Gullans, S. R.
Affiliations
  • Massachusetts General Hospital (US)
  • Brigham and Women's Hospital (US)
  • Message Pharmaceuticals (United States) (US)
  • Indiana University Indianapolis (US)
Corresponding author
Rogers, Jack T.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2002-11
Volume
277
Issue
47
Pages
45518-45528
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2141150496
Cited by
551
References
48
Citations by year
2026: 11 · 2025: 20 · 2024: 21 · 2023: 21 · 2022: 19 · 2021: 26 · 2020: 20 · 2019: 27 · 2018: 23 · 2017: 23 · 2016: 20 · 2015: 24 · 2014: 21 · 2013: 28 · 2012: 36
FWCI
8.47
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5k01mh002001-05)
  • National Institute of Mental Health (5K01MH02001)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
iron-responsive element, amyloid precursor protein, 5' untranslated region, iron homeostasis, iron regulatory proteins, iron chelation, deferoxamine, clioquinol, interleukin-1, translational regulation, Alzheimer's disease, beta-amyloid peptide, RNA secondary structure
MeSH terms
Alzheimer Disease, Animals, Base Sequence, Calcium, Deferoxamine, Enhancer Elements, Genetic, Gene Expression Regulation, Humans, Interleukin-1, Clioquinol, Iron, Iron Chelating Agents, Magnesium, Molecular Sequence Data, Nucleic Acid Conformation, RNA, Messenger, Protein Biosynthesis, Tumor Cells, Cultured, Amyloid beta-Protein Precursor, Genes, Reporter, 5' Untranslated Regions, Response Elements, Mice

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