IRON REGULATION OF GENE EXPRESSION

Summary

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

Top Publications

  1. pmc Molecular control of vertebrate iron homeostasis by iron regulatory proteins
    Michelle L Wallander
    Department of Oncological Sciences, University of Utah, 15N 2030E, Salt Lake City, UT 84112, USA
    Biochim Biophys Acta 1763:668-89. 2006
  2. pmc Alteration of iron regulatory proteins (IRP1 and IRP2) and ferritin in the brains of scrapie-infected mice
    Boe 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
  3. pmc HOIL-1 is not required for iron-mediated IRP2 degradation in HEK293 cells
    Kimberly 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
  4. ncbi An iron enhancer element in the FTN-1 gene directs iron-dependent expression in Caenorhabditis elegans intestine
    S 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
  5. pmc Iron-independent phosphorylation of iron regulatory protein 2 regulates ferritin during the cell cycle
    Michelle 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
  6. pmc Control of iron homeostasis by an iron-regulated ubiquitin ligase
    Ajay A Vashisht
    Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
    Science 326:718-21. 2009
  7. pmc Mammalian iron metabolism and its control by iron regulatory proteins
    Cole 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

Detail Information

Publications7

  1. pmc Molecular control of vertebrate iron homeostasis by iron regulatory proteins
    Michelle L Wallander
    Department of Oncological Sciences, University of Utah, 15N 2030E, Salt Lake City, UT 84112, USA
    Biochim Biophys Acta 1763:668-89. 2006
    ....
  2. pmc Alteration of iron regulatory proteins (IRP1 and IRP2) and ferritin in the brains of scrapie-infected mice
    Boe 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...
  3. pmc HOIL-1 is not required for iron-mediated IRP2 degradation in HEK293 cells
    Kimberly 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...
  4. ncbi An iron enhancer element in the FTN-1 gene directs iron-dependent expression in Caenorhabditis elegans intestine
    S 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...
  5. pmc Iron-independent phosphorylation of iron regulatory protein 2 regulates ferritin during the cell cycle
    Michelle 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...
  6. pmc Control of iron homeostasis by an iron-regulated ubiquitin ligase
    Ajay 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...
  7. pmc Mammalian iron metabolism and its control by iron regulatory proteins
    Cole 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...

Research Grants30

  1. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  2. Center for Neuroplasticity at the University of Puerto Rico
    Steven N Treistman; Fiscal Year: 2013
    ..This UPR COBRE Center should define pathways and benchmarks for basic and translational research across the UPR system for the next decades. ..
  3. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  4. Investigating the role of the cell cycle protein E2F1 in HIV-induced neurotoxicit
    Jacob Zyskind; Fiscal Year: 2013
    ..We believe that defining its contribution to neuronal loss will lead to novel therapeutic strategy of targeting E2F1 to prevent the neuronal damage and subsequent cognitive decline characterized by HIV-associated dementia. ..
  5. The Role of DRP-1 and Mitochondrial Fission in Pulmonary Arterial Hypertension
    Stephen L Archer; Fiscal Year: 2013
    ..This is the first study to exploit PAH's reliance on rapid fission to devise novel anti-fission, anti-proliferative therapies for PAH. ..
  6. Regulation of Antioxidant Genes and Oxidative Stress
    Yoshiaki Tsuji; Fiscal Year: 2013
    ..This proposal will also investigate the common regulatory mechanism of ferritin and other antioxidant genes that are involved in cellular defense mechanisms against oxidative stress. ..
  7. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  8. Regulation of the cell cycle by SCF and APC/C ubiquitin ligases
    Michele Pagano; Fiscal Year: 2013
    ..Given its critical role, the ubiquitin system is often deregulated in cancer cells. Thus, it is anticipated that the results of the proposed studies will have an impact on both basic science and cancer biology. ..
  9. Spatial and Temporal Regulation of Angiogenesis
    HAROLD FISHER DVORAK; Fiscal Year: 2013
    ..abstract_text> ..
  10. Role of 11q23 Chromosome Abnormalities in the Causation of Acute Leukemia
    Carlo M Croce; Fiscal Year: 2013
    ..abstract_text> ..
  11. Molecular Genetics of Sideroblastic Anemia
    Mark D Fleming; Fiscal Year: 2013
    ..In both cases, we expect to learn more about mitochondrial iron metabolism, the SAs and approaches to therapy. ..
  12. Iron in the pathogenesis of Friedreich's ataxia
    ARNULF HANS WERNER KOEPPEN; Fiscal Year: 2013
    ..The work is clinically relevant because it will resolve questions about iron in the formal pathogenesis and natural history of FRDA, and the potential value of iron chelation. ..