Iron has an essential role in many biological processes, including DMA synthesis/respiration, the tricarboxylic acid cycle, oxygen transport, heme synthesis and photosynthesis. But iron can also be toxic due to its ability to generate free radicals that damage macromolecules in cells. Consequently, organisms have evolved precise mechanisms to sense, acquire and store iron. Our goal is to learn more about how eukaryotic cells sense iron, generate a signal and transduce the signal into regulating iron homeostasis. Specifically, we are interested in understanding how transcription factors sense iron, and regulate gene expression in animal cells. While iron-mediated transcription factors have been identified in fungi and plants, little is known about the mechanisms and the proteins regulating iron-mediated transcriptional regulation in animal cells. We have discovered that Caenorhabditis elegans express ferritin (CeFTN-1 and CeFTN-2), which are key iron storage proteins. Our data shows that Ceftn-1 and Ceftn-2 are transcriptionally regulated by iron, and that cis-regulatory sequences present in their 5'upstream regions are required for this regulation. We propose to identify the cis-regulatory sequences and the iron-sensing transcription factor that binds these elements, and to determine how this transcription factor senses iron. We will also identify other C. elegans genes involved in iron signaling pathways. C. elegans offers a complementary approach to iron metabolic studies in other organisms, in that they are amenable to genetic analysis, they have organ/tissue systems, and they have homologs of genes encoding proteins involved in mammalian iron homeostasis.
The specific aims are 1) to characterize cis-acting iron-regulatory elements in Ceftn-1 and Ceftn-2 promoters, 2) to purify the C. elegans transcription factor that regulates the Ceftn-1 and Ceftn-2 genes, and to determine how this factor controls ferritin expression, and 3) to identify genes involved in iron signaling pathways in C. elegans using a green fluorescence protein (GFP)-based screen.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Erythrocyte and Leukocyte Biology Study Section (ELB)
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Wright, Daniel G
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University of Utah
Internal Medicine/Medicine
Schools of Medicine
Salt Lake City
United States
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Anderson, Cole P; Shen, Macy; Eisenstein, Richard S et al. (2012) Mammalian iron metabolism and its control by iron regulatory proteins. Biochim Biophys Acta 1823:1468-83
Romney, Steven Joshua; Newman, Ben S; Thacker, Colin et al. (2011) HIF-1 regulates iron homeostasis in Caenorhabditis elegans by activation and inhibition of genes involved in iron uptake and storage. PLoS Genet 7:e1002394
Romney, S Joshua; Thacker, Colin; Leibold, Elizabeth A (2008) An iron enhancer element in the FTN-1 gene directs iron-dependent expression in Caenorhabditis elegans intestine. J Biol Chem 283:716-25