A5043912410- RNA modifications and cancer
- Iron Metabolism and Disorders
- RNA and protein synthesis mechanisms
- Trace Elements in Health
- RNA Research and Splicing
- Hemoglobinopathies and Related Disorders
- Genetics, Aging, and Longevity in Model Organisms
- RNA regulation and disease
- Mitochondrial Function and Pathology
- Nuclear Structure and Function
- Cancer-related gene regulation
- Birth, Development, and Health
- Renal cell carcinoma treatment
- Cancer, Hypoxia, and Metabolism
- Erythropoietin and Anemia Treatment
- Plant Micronutrient Interactions and Effects
- Neurological diseases and metabolism
- Hemoglobin structure and function
- Ferroptosis and cancer prognosis
- Molecular Biology Techniques and Applications
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Metalloenzymes and iron-sulfur proteins
- Neuroscience of respiration and sleep
- Folate and B Vitamins Research
University of Utah
2006-2022
Kagawa University
2008
Pratt Institute
2008
Weatherford College
1994
Massachusetts Institute of Technology
1987-1988
Jean Mayer Human Nutrition Research Center on Aging
1987
Tufts University
1984
The mRNAs for the heavy and light subunits of iron-storage protein ferritin occur in cells largely as inactive ribonucleoprotein particles, which are recruited translation when iron enters cell. Cytoplasmic extracts from rat tissues hepatoma were shown by an electrophoretic separation procedure to form RNA-protein complexes involving a highly conserved sequence 5' untranslated region both heavy- light-subunit mRNAs. pattern complex formation was affected pretreatment rats or with iron....
Eukaryotic cells require iron for survival and have developed regulatory mechanisms maintaining appropriate intracellular concentrations. The degradation of protein 2 (IRP2) in iron-replete is a key event this pathway, but the E3 ubiquitin ligase responsible its proteolysis has remained elusive. We found that SKP1-CUL1-FBXL5 complex associates with promotes iron-dependent ubiquitination IRP2. F-box substrate adaptor FBXL5 was degraded upon oxygen depletion process required an iron-binding...
Iron regulatory proteins (IRP1 and IRP2) are RNA-binding that bind to specific structures, termed iron-responsive elements (IREs), located in the 5′- or 3′-untranslated regions of mRNAs encode involved iron homeostasis. IRP1 IRP2 RNA binding activities regulated by iron; IREs with high affinity iron-depleted cells low iron-repleted cells. The decrease activity occurs a switch between apoprotein 4Fe-4S forms, without changes levels, whereas reflects reduction levels. To determine mechanism...
Iron-responsive element-binding proteins (IRE-BPs) are cytosolic that bind to a conserved RNA stem-loop, termed the iron-responsive element (IRE), is located in 5'- or 3'-untranslated regions of mRNAs involved iron metabolism. Binding IRE-BP 5'-IREs represses translation, whereas binding 3'-IREs stabilizes mRNA. The previously identified (BP1) contains 4Fe-4S cluster and has sequence homology mitochondrial aconitase. important for iron-dependent regulation: BP1 containing low affinity IRE...
Abstract Clear cell renal carcinoma (ccRCC), the most common form of kidney cancer, is typically initiated by inactivation von Hippel Lindau ( VHL) gene, which results in constitutive activation hypoxia inducible factors, HIF-1α and HIF-2α. Using a high throughput screen, we identify novel compounds that decrease HIF-1/2α levels induce ferroptosis targeting Iron Sulfur Cluster Assembly 2 (ISCA2), component late mitochondrial (L-ISC) assembly complex. ISCA2 inhibition either pharmacologically...
Iron-regulatory proteins 1 and 2 (IRP1 IRP2) are RNA-binding that post-transcriptionally regulate the expression of mRNAs code for involved in maintenance iron energy homeostasis. Here we show hypoxia differentially regulates RNA binding activities IRP1 IRP2 human 293 mouse Hepa-1 cells. In contrast to IRP1, where hypoxic exposure decreases activity, increases activity. The increase activity results from increased protein levels. Cobalt, which mimics by activation hypoxia-inducible factor...
A family of noncoding mRNA sequences, iron-responsive elements (IREs), coordinately regulate several mRNAs through binding a mRNA-specific proteins, iron regulatory proteins (IRPs). IREs are hairpins with constant terminal loop and base-paired stems interrupted by an internal loop/bulge (in ferritin mRNA) or C-bulge m-aconitase, erythroid aminolevulinate synthase, transferrin receptor mRNAs). IRP2 requires the conserved C-G base pair in loop, whereas IRP1 occurs engineered U-A. Here we show...
Iron regulatory protein 2 (IRP2) is a central regulator of cellular iron homeostasis due to its regulation specific mRNAs encoding proteins uptake and storage. regulates IRP2 by mediating rapid proteasomal degradation, where hypoxia the mimetics CoCl2 desferrioxamine (DFO) stabilize it. Previous studies showed that iron-mediated degradation requires presence critical cysteines reside within 73-amino acid unique region. Here we show mutant lacking this region degraded at rate similar...
Abstract The perinatal brain requires a tightly regulated iron transport system. Iron regulatory proteins (IRPs) 1 and 2 are cytosolic that regulate the stability of mRNA for two major cellular transporters, transferrin receptor (TfR) divalent metal transporter‐1 (DMT‐1). We studied localization IRPs, their change in expression during development, relationship to TfR DMT‐1 rat between postnatal days (PND) 5 15. Twelve‐micron frozen coronal sections fixed tissue were obtained from...
Iron regulatory proteins (IRP1 and IRP2) are RNA-binding that bind to stem-loop structures, termed iron-responsive elements (IREs), present in either the 5'- or 3'-untranslated regions of specific mRNAs. The binding IRPs 5'-IREs inhibits translation mRNA, whereas 3'-IREs stabilizes mRNA. To study structure regulation IRP2, we isolated cDNAs for rat human IRP2. derived amino acid sequence IPR2 is 93% identical with IRP2 lower eukaryotes, indicating highly conserved. IRP1 share 61% overall...
The synthesis of both transferrin receptor (TfR) and ferritin is regulated post-transcriptionally by iron. This mediated iron responsive elements (IRES) in the 5′- 3′-untranslated regions, respectively, TfR mRNAs. Although these IRES have different sequences, they form a characteristic stem-loop. We used competttion assays partial peptide mapping UV-crosslinked IRE-protein complexes to show that cytosolic protein binding 5′-IRE, iron-responsive element (IRE-BP), also binds 3′-IRES. To...
Abstract Regulation of cellular iron homeostasis is crucial as both excess and deficiency cause hematological neurodegenerative diseases. Here we show that mice lacking iron-regulatory protein 2 (Irp2), a regulator homeostasis, develop diabetes. Irp2 post-transcriptionally regulates the iron-uptake transferrin receptor 1 (TfR1) iron-storage ferritin, dysregulation these proteins due to loss causes functional in β cells. This impairs Fe–S cluster biosynthesis, reducing function Cdkal1, an...
Given the important relationship between O2 and iron (Fenton chemistry) a study was undertaken to characterize effects of hypoxia, as well subsequent reoxygenation, on iron-regulatory proteins 1 2 (IRP1 IRP2) in rat hepatoma cell line. IRP1 IRP2 are cytosolic RNA-binding that bind RNA stem-loops located 5′- or 3′-untranslated regions specific mRNAs encoding involved homeostasis. In cells exposed binding decreased ∼2.8-fold after 6-h exposure 3% O2. Hypoxic inactivation abolished when were...
The iron storage protein ferritin consists of two types subunits different molecular weight, heavy (H) and light (L).The rat genome contains approximately 20 copies the L-subunit gene, which we have sequenced seven.One is an expressed gene containing three introns located between a- helical domains protein.The remaining six characteristics processed pseudogenes.Sequence divergence suggest that these pseudogenes arose 3-12 X 10' years ago, well within 30 lo6 mouse.By using intron probes...
Ferritin, an iron-storage protein found in all life forms examined, is composed of varying proportions two subunits different molecular weight, heavy (H) and light (L). Using cDNA clones, we have determined the nucleotide sequence corresponding to mRNA L-subunit rat liver ferritin. The coding region 546 nucleotides (182 amino acids) flanked by 5‘- 3‘ -untranslated regions approximately 130 150 nucleotides, respectively. acid derived from reading frame showed 88% 82% homology, respectively,...
Caenorhabditis elegans ftn-1 and ftn-2, which encode the iron-storage protein ferritin, are transcriptionally inhibited during iron deficiency in intestine. Intestinal specific transcription is dependent on binding of ELT-2 to GATA sites an iron-dependent enhancer (IDE) located ftn-2 promoters, but mechanism for regulation unknown. Here, we identify HIF-1 (hypoxia-inducible factor -1) as a negative regulator ferritin transcription. binds hypoxia-response elements (HREs) IDE vitro vivo....
Iron Regulatory Protein 2 (Irp2, Ireb2) is a central regulator of cellular iron homeostasis in vertebrates. Two global knockout mouse models have been generated to explore the role Irp2 regulating metabolism. While both show that loss results microcytic anemia and altered body distribution, discrepant drawn into question brain One model shows aged deficient mice develop adult-onset progressive neurodegeneration associated with axonal degeneration Purkinje cells nervous system. These...