Post-Transcriptional Regulation of Human Iron Metabolism by Iron Regulatory Proteins

2002 ◽  
Vol 29 (3) ◽  
pp. 309-314 ◽  
Author(s):  
Tracey A. Rouault
Keyword(s):  
Transcriptional Regulation ◽  
Iron Metabolism ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins ◽  
Post Transcriptional Regulation

scholarly journals Renal Iron Metabolism: Transferrin Iron Delivery and the Role of Iron Regulatory Proteins

2007 ◽  
Vol 18 (2) ◽  
pp. 401-406 ◽  
Author(s):  
Deliang Zhang ◽  
Esther Meyron-Holtz ◽  
Tracey A. Rouault
Keyword(s):  
Iron Metabolism ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins ◽  
Iron Delivery

Dysfunction of Iron Metabolism and Iron-Regulatory Proteins in the Rat Hippocampus After Heat Stroke

Shock ◽  
2019 ◽  
Vol 51 (6) ◽  
pp. 780-786 ◽  
Author(s):  
Jing Liu ◽  
Mingsheng Wan ◽  
Yun Zhang ◽  
Shu Zhang ◽  
Hongying Zhang ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Heat Stroke ◽  
Rat Hippocampus ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins

Regulation of Flvcr by Macrophages in Response to Lipopolysaccharide

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2111-2111
Author(s):  
Mary Philip ◽  
Edison Y. Chiu ◽  
Janis L. Abkowitz
Keyword(s):  
Transcriptional Regulation ◽  
Pathogenic Bacteria ◽  
Regulatory Proteins ◽  
Regulatory Function ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Down Regulation ◽  
Iron Storage ◽  
Iron Regulatory Proteins ◽  
Downstream Signaling

Abstract Abstract 2111 Pathogenic bacteria must acquire iron from their hosts to survive and have evolved multiple mechanisms to capture iron or iron-containing heme from the bloodstream or tissues. In response, mammals have developed defense mechanisms to keep iron from pathogens. For example, in response to inflammatory cytokines, hepcidin secreted by the liver binds to the iron exporter ferroportin (FPN1), leading to FPN1 internalization and degradation, decreasing gastrointestinal iron absorption and increasing macrophage iron storage. Much of the body's iron stores are complexed in heme. The Feline leukemia virus, subgroup C (FeLV-C) receptor, FLVCR, is a heme export protein. We showed previously that FLVCR is required for the normal development of the erythroid [Science (2008)319:825] and T cell lineages [Blood (ASH Annual Meeting Abstracts)114:913,2009]. Although macrophages express high levels of FLVCR, the role of FLVCR in regulating heme-iron after infection remains unexplored. Other heme regulatory proteins, such as heme oxygenase-1 (HMOX1), a heme-degrading enzyme, are known to be transcriptionally regulated in macrophages in response to infection. We hypothesized that macrophages dynamically regulate Flvcr in response to bacterial infection. To test this hypothesis, we stimulated J774, a murine macrophage cell line, with lipopolysaccharide (LPS from E. coli O111:B4) at varying concentrations and durations. LPS, an outer membrane component from gram-negative bacteria, binds to Toll-like receptor 4 (TLR4) on macrophages and activates downstream signaling pathways. Using multiplex quantitative reverse transcription polymerase chain reaction (qRT-PCR), we measured mRNA levels of Flvcr, Hmox1, and Fpn1. We found that J774 cells down-regulated Flvcr transcript levels in response to LPS with a maximal decrease (69%) seen at 6–8 hours of stimulation. While the extent of Flvcr down-regulation was dose-responsive, a significant decrease (57%) occurred even with the lowest LPS dose (10 ng/ml). Macrophages decreased Fpn1 expression (71%) and increased Hmox1 expression (55%) in response to LPS stimulation as previously reported. Similar results were obtained with LPS from a different bacterial source (Salmonella minnesota Re595). We also performed these studies using primary macrophages cultured from murine bone marrow mononuclear cells and observed a similar decrease in Flvcr and Fpn1 (64 and 72%) and an increase in Hmox1 (40%) transcripts after stimulation with both O111:B4 and Re595 LPS. While Fpn1 transcriptional regulation by heme and oxidative stress has been studied, the mechanism by which LPS regulates Fpn1 transcription is less clear. The similar pattern and kinetics of LPS-induced Flvcr and Fpn1 expression changes raise the possibility that the same regulatory mechanism is responsible. Analysis of the human and mouse Flvcr promoter regions revealed several putative LPS downstream transcription factor binding sites including NF-κB, AP1, and C/EBPβ. In addition to transcriptional regulation, LPS downstream signaling could alter Flvcr and Fpn1 mRNA stability and translation, so we compared the 5' untranslated regions (UTR) and 3'UTR of murine Flvcr and Fpn1. We found little similarity between the 5'UTR of Flvcr and the 5'UTR of Fpn1, known to contain an iron-responsive element (IRE) and be regulated by iron via iron regulatory proteins (IRP). However, alignment of the 3'UTR from Flvcr and Fpn1 showed similarity (pair wise score 65). Both the Flvcr and Fpn1 3'UTR are predicted to have a high degree of secondary structure based on their large negative fold energies (−421.25 and −300.74 kcal/mol), further suggesting that these 3'UTR may have a regulatory function. Studies are underway to determine the roles of the Flvcr promoter, 5'UTR, and 3'UTR in LPS-induced down-regulation. This work suggests that LPS-induced down-regulation of Flvcr and Fpn1 might act in concert to decrease heme and iron export from macrophages and sequester iron from bacterial pathogens. Heme export control through FLVCR could serve as a novel mechanism of iron regulation in response to infection. Disclosures: No relevant conflicts of interest to declare.

Iron Regulatory Proteins in Systemic Iron Metabolism and Erythropoiesis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-22-SCI-22
Author(s):  
Matthias W. Hentze
Keyword(s):  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Mutant Mouse ◽  
Conflicts Of Interest ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins ◽  
Cellular Iron ◽  
Regulatory Systems ◽  
Biology I ◽  
Mouse Lines

Abstract Abstract SCI-22 Imbalances of iron homeostasis account for some of the most common human diseases. Pathologies can result from both iron deficiency or overload. The hepcidin/ferroportin and the IRE/IRP regulatory systems balance systemic and cellular iron metabolism, respectively, and understanding their points of intersection and crosstalk represents a major challenge in iron biology. I will discuss an emerging picture from studies with different mutant mouse lines according to which the “cellular” IRE/IRP system determines “set points” via its targets (including ferroportin and HIF2α). These are then subject to modulation via hepcidin in response to systemic cues. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The role of iron regulatory proteins in the control of iron metabolism in mammals

2011 ◽  
Vol 1 ◽  
pp. 66-75 ◽  
Author(s):  
Agnieszka Styś ◽  
Rafał R. Starzyński ◽  
Paweł Lipiński
Keyword(s):  
Iron Metabolism ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins

scholarly journals Iron-regulatory proteins: molecular biology and pathophysiological implications

2007 ◽  
Vol 9 (33) ◽  
pp. 1-13 ◽  
Author(s):  
Gaetano Cairo ◽  
Stefania Recalcati
Keyword(s):  
Cell Growth ◽  
Molecular Biology ◽  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Regulatory Proteins ◽  
Cellular Functions ◽  
Major Health ◽  
Iron Regulatory Proteins ◽  
Human Disorders ◽  
Apoptosis And Inflammation

AbstractIron is required for key cellular functions, and there is a strong link between iron metabolism and important metabolic processes, such as cell growth, apoptosis and inflammation. Diseases that are directly or indirectly related to iron metabolism represent major health problems. Iron-regulatory proteins (IRPs) 1 and 2 are key controllers of vertebrate iron metabolism and post-transcriptionally regulate expression of the major iron homeostasis genes. Here we discuss how dysregulation of the IRP system can result from both iron-related and unrelated effectors and explain how this can have important pathological consequences in several human disorders.

Iron regulatory protein-1 and -2: transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by iron regulatory proteins

Blood ◽  
2011 ◽  
Vol 118 (22) ◽  
pp. e168-e179 ◽  
Author(s):  
Mayka Sanchez ◽  
Bruno Galy ◽  
Bjoern Schwanhaeusser ◽  
Jonathon Blake ◽  
Tomi Bähr-Ivacevic ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Rna Binding ◽  
Isotope Labeling ◽  
Rna Binding Proteins ◽  
Regulatory Protein ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins ◽  
Ribonucleoprotein Complexes ◽  
Cellular Iron ◽  
Irp1 And Irp2

Abstract Iron regulatory proteins (IRPs) 1 and 2 are RNA-binding proteins that control cellular iron metabolism by binding to conserved RNA motifs called iron-responsive elements (IREs). The currently known IRP-binding mRNAs encode proteins involved in iron uptake, storage, and release as well as heme synthesis. To systematically define the IRE/IRP regulatory network on a transcriptome-wide scale, IRP1/IRE and IRP2/IRE messenger ribonucleoprotein complexes were immunoselected, and the mRNA composition was determined using microarrays. We identify 35 novel mRNAs that bind both IRP1 and IRP2, and we also report for the first time cellular mRNAs with exclusive specificity for IRP1 or IRP2. To further explore cellular iron metabolism at a system-wide level, we undertook proteomic analysis by pulsed stable isotope labeling by amino acids in cell culture in an iron-modulated mouse hepatic cell line and in bone marrow-derived macrophages from IRP1- and IRP2-deficient mice. This work investigates cellular iron metabolism in unprecedented depth and defines a wide network of mRNAs and proteins with iron-dependent regulation, IRP-dependent regulation, or both.

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