Genomes and Genes
IRON REGULATION OF GENE EXPRESSION
Principal Investigator: ELIZABETH ANN LEIBOLD
Abstract: DESCRIPTION (provided by applicant): Iron is essential for cell growth and proliferation due to its role as prosthetic group in proteins required for DNA synthesis and energy metabolism. In humans, cellular iron overload can result in diabetes mellitus and neurodegenerative disease, and is associated with an increased risk of cancer, while iron deficiency perinatally or postnatally can cause neurocognitive impairment, and deficiency in adults cause anemia. All organisms have therefore developed mechanisms to sense, acquire and store iron. In vertebrates, iron metabolism is controlled by iron-regulatory protein 2 (IRP2). IRP2 is a RNA-binding protein that binds to iron-responsive elements (IREs) located in mRNAs of proteins involved in iron uptake, sequestration and export. IRP2 binding to IREs regulates the translation or stability of mRNAs. IRP2 deficiency in mice impairs iron homeostasis in multiple tissues, and leads to hematological, neurodegenerative and metabolic disorders. We have identified novel pathways and proteins regulating IRP2 function: iron-dependent proteolysis by an iron-regulated FBXL5 ubiquitin ligase and iron-independent regulation of RNA-binding activity by cyclin-dependent kinase 1 (CDK1) phosphorylation during the cell cycle. Our goals are to determine how iron regulates IRP2 stability and how IRP2 phosphorylation regulates cell cycle progression. PUBLIC HEALTH RELEVANCE: Millions of patients suffer from diseases involving iron overload and deficiency. The nutritional requirement for iron is due to its role such essential cellular processes as cell division and energy production. Iron dysregulation leads to hematological, metabolic and neurodegenerative diseases, and increases the risk of cancer. Because of the adverse impact of iron disorders on health, understanding how cells and tissues respond to iron overload and deficiency is important for treating these disorders. Iron regulatory protein 2 (IRP2) is a key regulator of cellular iron metabolism. We have discovered two novel mechanisms that regulate IRP2 in proliferating cells and in iron overloaded cells. Increased knowledge of the mechanism by which IRP2 regulates iron balance and cell proliferation is important for developing therapeutics that can be used to target cancer cells and treat iron disorders.
Funding Period: 1991-01-01 - 2015-06-30
more information: NIH RePORT
- Molecular control of vertebrate iron homeostasis by iron regulatory proteinsMichelle L Wallander
Department of Oncological Sciences, University of Utah, 15N 2030E, Salt Lake City, UT 84112, USA
Biochim Biophys Acta 1763:668-89. 2006....
- Alteration of iron regulatory proteins (IRP1 and IRP2) and ferritin in the brains of scrapie-infected miceBoe Hyun Kim
Ilsong Institute of Life Science, Academy of Science, Hallym University, Dongan Gu, Anyang, Kyounggi do 431 060, South Korea
Neurosci Lett 422:158-63. 2007..These results suggest that alteration of iron metabolism contributes to development of neurodegeneration and that some protective mechanisms against iron-induced oxidative damage may occur during the pathogenesis of TSEs...
- HOIL-1 is not required for iron-mediated IRP2 degradation in HEK293 cellsKimberly B Zumbrennen
Eccles Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, UT 84112, USA
Biochim Biophys Acta 1783:246-52. 2008..These data demonstrate that HOIL-1 is not required for iron-dependent degradation of IRP2 in HEK293 cells, and suggest that a HOIL-1 independent mechanism is used for IRP2 degradation in most cell types...
- An iron enhancer element in the FTN-1 gene directs iron-dependent expression in Caenorhabditis elegans intestineS Joshua Romney
Eccles Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City 84112, USA
J Biol Chem 283:716-25. 2008..These data demonstrate that the activation of ftn-1 and ftn-2 transcription by iron requires ELT-2 and that the IDE functions as an iron-dependent enhancer in intestine...
- Iron-independent phosphorylation of iron regulatory protein 2 regulates ferritin during the cell cycleMichelle L Wallander
Department of Oncological Sciences, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA
J Biol Chem 283:23589-98. 2008..These data show that reversible phosphorylation of IRP2 during G(2)/M has a role in modulating the iron-independent expression of ferritin and other IRE-containing mRNAs during the cell cycle...
- Control of iron homeostasis by an iron-regulated ubiquitin ligaseAjay A Vashisht
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Science 326:718-21. 2009..Thus, iron homeostasis is regulated by a proteolytic pathway that couples IRP2 degradation to intracellular iron levels through the stability and activity of FBXL5...
- Mammalian iron metabolism and its control by iron regulatory proteinsCole P Anderson
Department of Oncological Sciences, University of Utah, 15 N 2030 E, Salt Lake City, UT 84112, USA
Biochim Biophys Acta 1823:1468-83. 2012..A mechanistic understanding of IRP regulation will likely yield important insights into the basis of disorders of iron metabolism. This article is part of a Special Issue entitled: Cell Biology of Metals...
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