This project is aimed towards a molecular understanding of the basis of intracellular iron metabolism. A molecular genetic examination of human ferritin has set the basis for defining a cis/trans regulatory model for the post-transcriptional regulation of this critical protein of intracellular iron metabolism. Iron regulates the translation of the mRNA encoding ferritin by virtue of its ability to alter the binding activity of a cytosolic protein that binds to a specific RNA sequence contained within the ferritin message. A complete description of this RNA regulatory element, the RNA binding protein, and how iron regulates their interaction will provide the first complete description of a translational control system in higher eukaryotic cells. In order to elucidate previously unknown components of the human cellular iron metabolism, we have established the mechanism for the uptake of iron in the genetically manipulatable simple eukaryote, Saccharomyces cerevisiae. This has led to the identification of a reductase/transporter system to explain the transmembrane, regulated uptake of iron in this organism.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
1990
Total Cost
Indirect Cost
City
State
Country
United States
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Rouault, Tracey A; Tong, Wing-Hang (2009) Tangled up in red: intertwining of the heme and iron-sulfur cluster biogenesis pathways. Cell Metab 10:80-1
Tong, Wing-Hang; Rouault, Tracey A (2007) Metabolic regulation of citrate and iron by aconitases: role of iron-sulfur cluster biogenesis. Biometals 20:549-64
Crooks, Daniel R; Ghosh, Manik C; Braun-Sommargren, Michelle et al. (2007) Manganese targets m-aconitase and activates iron regulatory protein 2 in AF5 GABAergic cells. J Neurosci Res 85:1797-809
Missirlis, Fanis; Kosmidis, Stylianos; Brody, Tom et al. (2007) Homeostatic mechanisms for iron storage revealed by genetic manipulations and live imaging of Drosophila ferritin. Genetics 177:89-100
Zhang, Deliang; Meyron-Holtz, Esther; Rouault, Tracey A (2007) Renal iron metabolism: transferrin iron delivery and the role of iron regulatory proteins. J Am Soc Nephrol 18:401-6
Smith, Sophia R; Ghosh, Manik C; Ollivierre-Wilson, Hayden et al. (2006) Complete loss of iron regulatory proteins 1 and 2 prevents viability of murine zygotes beyond the blastocyst stage of embryonic development. Blood Cells Mol Dis 36:283-7
Lind, Maria I; Missirlis, Fanis; Melefors, Ojar et al. (2006) Of two cytosolic aconitases expressed in Drosophila, only one functions as an iron-regulatory protein. J Biol Chem 281:18707-14
Missirlis, Fanis; Holmberg, Sara; Georgieva, Teodora et al. (2006) Characterization of mitochondrial ferritin in Drosophila. Proc Natl Acad Sci U S A 103:5893-8
Rouault, Tracey A; Cooperman, Sharon (2006) Brain iron metabolism. Semin Pediatr Neurol 13:142-8
Rouault, Tracey A (2006) Biochemistry. If the RNA fits, use it. Science 314:1886-7

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