The role of iron regulatory proteins in mammalian iron homeostasis and disease

2006 ◽  
Vol 2 (8) ◽  
pp. 406-414 ◽  
Author(s):  
Tracey A Rouault
Keyword(s):  
Iron Homeostasis ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins

Iron homeostasis: new tales from the crypt

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4020-4027 ◽  
Author(s):  
Cindy N. Roy ◽  
Caroline A. Enns
Keyword(s):  
Iron Uptake ◽  
Iron Transport ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Hereditary Hemochromatosis ◽  
The Body ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins ◽  
Duodenal Epithelium ◽  
Related Proteins

Abstract The enterocyte is a highly specialized cell of the duodenal epithelium that coordinates iron uptake and transport into the body. Until recently, the molecular mechanisms underlying iron absorption and iron homeostasis have remained a mystery. This review focuses on the proteins and regulatory mechanisms known to be present in the enterocyte precursor cell and in the mature enterocyte. The recent cloning of a basolateral iron transporter and investigations into its regulation provide new insights into possible mechanisms for iron transport and homeostasis. The roles of proteins such as iron regulatory proteins, the hereditary hemochromatosis protein (HFE)–transferrin receptor complex, and hephaestin in regulating this transporter and in regulating iron transport across the intestinal epithelium are discussed. A speculative, but testable, model for the maintenance of iron homeostasis, which incorporates the changes in the iron-related proteins associated with the life cycle of the enterocyte as it journeys from the crypt to the tip of the villous is proposed.

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 Nitric Oxide–Mediated Induction of Ferritin Synthesis in J774 Macrophages by Inflammatory Cytokines: Role of Selective Iron Regulatory Protein-2 Downregulation

Blood ◽  
1998 ◽  
Vol 91 (3) ◽  
pp. 1059-1066 ◽  
Author(s):  
Stefania Recalcati ◽  
Donatella Taramelli ◽  
Dario Conte ◽  
Gaetano Cairo
Keyword(s):  
Nitric Oxide ◽  
Posttranscriptional Regulation ◽  
Iron Homeostasis ◽  
Regulatory Protein ◽  
Intracellular Iron ◽  
Iron Regulatory Proteins ◽  
Ferritin Synthesis ◽  
Direct Demonstration ◽  
J774 Cells

Cytokine-treated macrophages represent a useful model to unravel the molecular basis of reticuloendothelial (RE) iron retention in inflammatory conditions. In the present study, we showed that stimulation of murine macrophage J774 cells with interferon (IFN)-γ/lipopolysaccharide (LPS) resulted in a nitric oxide-dependent modulation of the activity of iron regulatory proteins (IRP)-1 and 2, cytoplasmic proteins which, binding to RNA motifs called iron responsive elements (IRE), control ferritin translation. Stimulation with cytokines caused a small increase of IRP-1 activity and a strong reduction of IRP-2 activity accompanied by increased ferritin synthesis and accumulation. Cytokines induced only a minor increase of H chain ferritin mRNA, thus indicating that IRP-2–mediated posttranscriptional regulation plays a major role in the control of ferritin expression. This was confirmed by direct demonstration that the translational repression function of IRP was impaired in stimulated cells. In fact, translation in cell-free extracts of a reporter transcript under the control of an IRE sequence was repressed less efficiently by IRP-containing lysates from cytokine-treated cells than by lysates from control cells. Our findings throw light on the role of IRP-2 showing that: (1) this protein responds to a stimulus in opposite fashion to IRP-1; (2) when abundantly expressed, as in J774 cells, IRP-2 is sufficient to regulate intracellular iron metabolism in living cells; and (3) by allowing increased ferritin synthesis, IRP-2 may play a role in the regulation of iron homeostasis in RE cells during inflammation.

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

HFE Downregulates Iron Uptake From Transferrin and Induces Iron-Regulatory Protein Activity in Stably Transfected Cells

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3915-3921 ◽  
Author(s):  
H.D. Riedel ◽  
M.U. Muckenthaler ◽  
S.G. Gehrke ◽  
I. Mohr ◽  
K. Brennan ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Regulatory Protein ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Iron Regulatory Proteins ◽  
Cellular Iron

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder of iron metabolism. More than 80% of HH patients are homozygous for a point mutation in a major histocompatibility complex (MHC) class I type protein (HFE), which results in a lack of HFE expression on the cell surface. A previously identified interaction of HFE and the transferrin receptor suggests a possible regulatory role of HFE in cellular iron absorption. Using an HeLa cell line stably transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron uptake. We demonstrate that the overproduction of HFE results in decreased iron uptake from diferric transferrin. Moreover, HFE expression activates the key regulators of intracellular iron homeostasis, the iron-regulatory proteins (IRPs), implying that HFE can affect the intracellular “labile iron pool.” The increase in IRP activity is accompanied by the downregulation of the iron-storage protein, ferritin, and an upregulation of transferrin receptor levels. These findings are discussed in the context of the pathophysiology of HH and a possible role of iron-responsive element (IRE)-containing mRNAs.

Iron homeostasis: new tales from the crypt

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4020-4027 ◽  
Author(s):  
Cindy N. Roy ◽  
Caroline A. Enns
Keyword(s):  
Iron Uptake ◽  
Iron Transport ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Hereditary Hemochromatosis ◽  
The Body ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins ◽  
Duodenal Epithelium ◽  
Related Proteins

The enterocyte is a highly specialized cell of the duodenal epithelium that coordinates iron uptake and transport into the body. Until recently, the molecular mechanisms underlying iron absorption and iron homeostasis have remained a mystery. This review focuses on the proteins and regulatory mechanisms known to be present in the enterocyte precursor cell and in the mature enterocyte. The recent cloning of a basolateral iron transporter and investigations into its regulation provide new insights into possible mechanisms for iron transport and homeostasis. The roles of proteins such as iron regulatory proteins, the hereditary hemochromatosis protein (HFE)–transferrin receptor complex, and hephaestin in regulating this transporter and in regulating iron transport across the intestinal epithelium are discussed. A speculative, but testable, model for the maintenance of iron homeostasis, which incorporates the changes in the iron-related proteins associated with the life cycle of the enterocyte as it journeys from the crypt to the tip of the villous is proposed.

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.

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