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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our groups have previously identified in independent studies the gene At2g28160 as a central transcription factor that is required for up-regulation of iron deficiency responses in Arabidopsis roots. At2g28160 has been named in different ways in our previous studies, namely FRU=FER-LIKE REGULATOR OF IRON UPTAKE [M. Jakoby, H.Y. Wang, W. Reidt, B. Weisshaar, P. Bauer, FRU (BHLH029) is required for induction of iron mobilization genes in Arabidopsis thaliana, FEBS Lett. 577 (2004) 528-534], BHLH029 [M.A. Heim, M. Jakoby, M. Werber, C. Martin, B. Weisshaar, P.C. Bailey, The basic helix-loop-helix transcription factor family in plants: a genome-wide study of protein structure and functional diversity, Mol. Biol. Evol. 20 (2003) 735-747; Y.X. Yuan, J. Zhang, D.W. Wang, H.Q. Ling, AtbHLH29 of Arabidopsis thaliana is a functional ortholog of tomato FER involved in controlling iron acquisition in strategy I plants, Cell Res. 15 (2005) 613-621] or FIT1=Fe-DEFICIENCY-INDUCED TRANSCRIPTION FACTOR1 [E.P.Colangelo, M.L. Guerinot, The essential basic helix-loop-helix protein FIT1 is required for the iron deficiency response, Plant Cell 12 (2004) 3400-3412.] To avoid any confusion in the future we propose a common name for At2g28160 in Arabidopsis, namely FIT=FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR.
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PMID:FIT, the FER-LIKE IRON DEFICIENCY INDUCED TRANSCRIPTION FACTOR in Arabidopsis. 1746 30

Autoimmune atrophic gastritis is encountered in 20-27% of patients with obscure, or refractory iron deficiency anemia and is 4 to 6 times more common than celiac disease causing unexplained iron deficiency. The unique clinical features of iron deficiency anemia associated with achlorhydria and mucosal atrophy sparing the gastric antrum have all been accurately described by Faber and others over 100 years ago, including its refractoriness to oral iron treatment, female predominance, relatively young age, increased prevalence of thyroid disease and tendency to progress to pernicious anemia. A significant new development is the relation between autoimmune gastritis and Helicobacter pylori infection. H. pylori per se impairs gastric acid secretion and it is quite likely that a proportion of patients described originally as achylia gastrica represented H. pylori and not autoimmune gastritis. The demonstration of H. pylori antibodies in atrophic gastritis directed against epitopes on gastric mucosal cells implies an autoimmune mechanism triggered by H. pylori and directed against gastric parietal cells by antigenic mimicry of H+K+-ATPase, the most common autoantigen in pernicious anemia. These findings introduce a new element into the 100-year-old saga of achylia gastrica and open new options for its prevention and management.
Blood Cells Mol Dis
PMID:The anemia of achylia gastrica revisited. 1749 46

Mammalian iron homeostasis must be meticulously regulated so that this essential element is available for use, but at the same time prevented from promoting the formation of toxic radicals. Controlling the entry of iron into blood plasma is the main mechanism by which iron stores in the body are physiologically manipulated and regulated. Defects in iron acquisition at the cellular and systemic levels lead to human disorders, which involve either iron overload or iron deficiency. Discoveries of iron transporters and insights into their regulation have provided important information about iron metabolism and genetic iron disorders.
Nat Rev Mol Cell Biol 2008 Jan
PMID:Regulation of iron acquisition and storage: consequences for iron-linked disorders. 1798 43

Anthracyclines are effective anticancer agents. However, their use is limited by cardiotoxicity, an effect linked to their ability to chelate iron and to perturb iron metabolism (Mol Pharmacol 68:261-271, 2005). These effects on iron-trafficking remain poorly understood, but they are important to decipher because treatment for anthracycline cardiotoxicity uses the chelator, dexrazoxane. Incubation of cells with doxorubicin (DOX) up-regulated mRNA levels of the iron-regulated genes transferrin receptor-1 (TfR1) and N-myc downstream-regulated gene-1 (Ndrg1). This effect was mediated by iron depletion, because it was reversed by adding iron and it was prevented by saturating the anthracycline metal binding site with iron. However, DOX did not act like a typical chelator, because it did not induce cellular iron mobilization. In the presence of DOX and (59)Fe-transferrin, iron-trafficking studies demonstrated ferritin-(59)Fe accumulation and decreased cytosolic-(59)Fe incorporation. This could induce cytosolic iron deficiency and increase TfR1 and Ndrg1 mRNA. Up-regulation of TfR1 and Ndrg1 by DOX was independent of anthracycline-mediated radical generation and occurred via hypoxia-inducible factor-1alpha-independent mechanisms. Despite increased TfR1 and Ndrg1 mRNA after DOX treatment, this agent decreased TfR1 and Ndrg1 protein expression. Hence, the effects of DOX on iron metabolism were complex because of its multiple effector mechanisms.
Mol Pharmacol 2008 Mar
PMID:Iron chelation by clinically relevant anthracyclines: alteration in expression of iron-regulated genes and atypical changes in intracellular iron distribution and trafficking. 1802 50

We studied the effect of iron deficiency, i.e., 24-h preincubation in iron-free medium, and the effect of high level of non-transferrin iron, i.e., the preincubation in ferric citrate medium containing 500 microM ferric citrate, on the expression of DMT1, Dcytb, ferroportin, hephaestin, and ceruloplasmin in various functional types of human cells. The expression of these proteins potentially involved in non-transferrin iron transport across cell membranes was tested on mRNA level by quantitative real-time PCR as well as on protein level by western blot analysis in Caco-2 (colorectal carcinoma), K562 (erythroleukemia), and HEP-G2 (hepatocellular carcinoma) cells. We found that changes in non-transferrin iron availability, i.e., iron deficiency and high level of non-transferrin iron, affect the expression of tested proteins in a cell type-specific manner. We also demonstrated that changes in the expression on mRNA level do not often correlate with relevant changes on protein level.
Mol Cell Biochem 2009 Jan
PMID:Differing expression of genes involved in non-transferrin iron transport across plasma membrane in various cell types under iron deficiency and excess. 1883 May 67

Soluble transferrin receptors have gained interest in the field of diagnosing anemias. Reference ranges differ according to the method used for the quantification of sTfR. We aim to explore the distributional properties and diagnostic performance of sTfR in pre-school healthy children as well as in children with beta-thalassemia carriers, iron deficiency with normal hematological phenotype (ID) and iron deficiency anemia (IDA). Circulating sTfR as well as biochemical and hematological indices were determined in 521 pre-school children and four groups (normal children, beta-thalassemia traits, ID and IDA) were formed. Diagnostic performance and distribution of sTfR according to age and in relation to several parameters were evaluated in every group. Three hundred eighty one children (261 normal, 60 beta-thalassemia traits, 44 ID and 16 IDA) aged 1-6 years were included. We found that distribution of sTfR differed significantly among the four groups (Kruskal Wallis p<0.001) with children in the normal group exhibiting lower concentrations compared to all other. A negative correlation between sTfR and age occurred in the normal (beta=-0.12, p<0.001) and the ID groups (beta=-0.13, p=0.035). In the beta-thal and IDA groups sTfR is correlated to HbA(2) (beta=0.34, p=0.001) and ferritin (Spearman's rho=-0.6, p=0.014) respectively. An area under the curve equal to 0.63 was achieved by sTfR in distinguishing between normal and ID children. Sensitivity and specificity were 70.5% and 50% respectively at a cut-off of 2.5 mg/l. Levels of sTfR are negatively correlated to age in pre-school children while dyserythropoietic procedures like beta-thal, ID, and IDA significantly affect them. These findings indicated that the accuracy of sTfR in diagnosing ID from normal children is limited. Standardization will allow the use of formulas that combine sTfR and ferritin which are of greater diagnostic value than sTfR alone.
Blood Cells Mol Dis
PMID:Serum transferrin receptors: Distribution and diagnostic performance in pre-school children. 1939 51

The maintenance of iron homeostasis is critical as both iron deficiency and iron excess are deleterious. In mammals, iron homeostasis is regulated systemically by the iron-hormone hepcidin, an acute-phase protein secreted by the liver which inhibits iron absorption and recycling. Cellularly, the interaction of iron regulatory proteins (IRP) 1 and 2 with iron-responsive elements controls the expression of target mRNAs encoding proteins of iron acquisition, storage, utilization, and export. These processes critically affect iron levels, which in turn impact on numerous aspects of inflammation. To explore the role of IRP1 and IRP2 in inflammation, IRP-deficient mice, i.e., mice with total and constitutive deficiency of either IRP, were subjected to acute aseptic local inflammation. Turpentine oil injection increases the expression of acute phase proteins in the liver and interleukin 6 levels in the serum of control mice. Both IRP-deficient mouse models mount the same responses, indicating that the treatment was efficient in all animals and that the acute phase response does not require expression of both IRPs. As expected, turpentine oil treatment enhances hepcidin mRNA expression in the liver of wild-type mice, associated with decreased serum iron levels. Importantly, Irp1 (-/-) and Irp2 (-/-) animals, respectively, display quantitatively similar hepcidin mRNA induction and the appropriate reduction of the serum iron values. Our data indicate that the response of Irp1 (-/-) and Irp2 (-/-) mice to acute local inflammation is largely preserved.
J Mol Med (Berl) 2009 Sep
PMID:In vivo role(s) of the iron regulatory proteins (IRP) 1 and 2 in aseptic local inflammation. 1953 74

Mutations leading to abrogation of matriptase-2 proteolytic activity in humans are associated with an iron-refractory iron deficiency anemia (IRIDA) due to elevated hepcidin levels. Here we describe two novel heterozygous mutations within the matriptase-2 (TMPRSS6) gene of monozygotic twin girls exhibiting an IRIDA phenotype. The first is the frameshift mutation (P686fs) caused by the insertion of the four nucleotides CCCC in exon 16 (2172_2173insCCCC) that is predicted to terminate translation before the catalytic serine. The second mutation is the di-nucleotide substitution c.467C>A and c.468C>T in exon 3 that causes the missense mutation A118D in the SEA domain of the extracellular stem region of matriptase-2. Functional analysis of both variant matriptase-2 proteases has revealed that they lead to ineffective suppression of hepcidin transcription. We also demonstrate that the A118D SEA domain mutation causes an intra-molecular structural imbalance that impairs matriptase-2 activation. Collectively, these results extend the pattern of TMPRSS6 mutations associated with IRIDA and functionally demonstrate that mutations affecting protease regions other than the catalytic domain may have a profound impact in the regulatory role of matriptase-2 during iron deficiency.
Hum Mol Genet 2009 Oct 01
PMID:Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms. 1959 82

The effects of diets with different Maillard reaction products (MRPs) content on biological iron utilization were compared using in vitro/in vivo assays. Diets were rich (brown diet, BD) or poor (white diet) in MRP. In vitro studies included iron solubility after in vitro digestion of diets and iron transport across Caco-2 cells. In the human assay 18 healthy adolescent males (11-14 years) participated in a 2-wk randomized two-period crossover trial. Subjects collected urine and faeces on the last 3 days of each dietary period, and fasting blood samples were obtained after periods. In vitro dietary iron availability was significantly lower with the BD than the white diet (9.52 and 12.92%, respectively), as a consequence of the lower iron solubility after the in vitro digestion, but not as a result of decreased transport of the remaining soluble iron. The BD consumption increased iron fecal excretion ( approximately 1.4-fold) and significantly decreased its bioavailability ( approximately 2.7-fold), mainly due to the effects found at digestive level. Serum biochemical parameters related to iron metabolism remained unaltered. It is concluded the presence of MRP in the diet negatively affects iron bioavailability. As iron deficiency may be related to learning impairment and to reductions of cognitive and physical functions, possible long-term effects of excessive MRP intake during adolescence warrant attention.
Mol Nutr Food Res 2009 Dec
PMID:Intake of Maillard reaction products reduces iron bioavailability in male adolescents. 1975 4

Male subjects with iron deficiency from the general population were examined for polymorphisms or sporadic mutations in TMPRSS6 to identify genetic risk factors for iron deficiency anemia. Three uncommon non-synonymous polymorphisms were identified, G228D, R446W, and V795I (allele frequencies 0.0074, 0.023 and 0.0074 respectively), of which the R446W polymorphism appeared to be overrepresented in the anemic population. In addition, three children with iron refractory iron deficiency anemia, and one sibling with iron responsive iron deficiency anemia were also examined for polymorphisms or sporadic mutations in TMPRSS6. Two children (family 1) were compound heterozygotes for a L674F mutation and a previously described splicing defect predicted to cause skipping of exon 13 (IVS13+1 G>A). One child from the second family was homozygous for a deletion (497T) causing a frameshift (L166X+36) and premature termination. The sibling and mother from the second family were compound heterozygotes for the L166X mutation and the uncommon R446W polymorphism. Although in vitro expression studies demonstrated that the R446W isoform was biologically similar to wildtype Tmprss6, clinical data indicate that the R446W produces a milder disease when carried in trans with severe mutation in Tmprss6. The four children carrying mutations in TMPRSS6 all exhibited inappropriately high urinary hepcidin levels for the degree of iron deficiency.
Blood Cells Mol Dis 2010 Jan 15
PMID:Polymorphisms and mutations of human TMPRSS6 in iron deficiency anemia. 1981 57


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