Abstract

This project is aimed at understanding the molecular basis of intracellular iron metabolism. The components of a post-transcriptional cis-trans regulatory model have been identified and characterized in previous years in this laboratory. Iron-responsive elements (IREs) are RNA stem-loops found in the 5' end of ferritin mRNA and the 3' end of transferrin receptor mRNA. We have cloned and expressed an iron-sensing protein, the iron- responsive element binding protein (IRE-BP) that binds IREs when iron levels are depleted, resulting in the translational inhibition of ferritin and stabilization of the mRNA half-life of the transferrin receptor. The IRE-BP is 30% identical in sequence to aconitase, a mitochondrial Krebs cycle enzyme containing cluster. The IRE-BP has aconitase activity, and in vitro manipulations of iron result in changes in RNA binding. A complete description of this """"""""iron switch"""""""" and the role of aconitase enzymatic activity in the function of the IRE-BP will lead to a more complete understanding of this complex RNA-protein regulatory interaction.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Intramural Research (Z01)
Project #
1Z01HD001602-07
Application #
3857169
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
Eunice Kennedy Shriver National Institute of Child Health & Human Development
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

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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