Iron regulation of transferrin receptor mRNA levels requires iron-responsive elements and a rapid turnover determinant in the 3′ untranslated region of the mRNA.

Casey, John; Koeller, D.M.; Ramin, V.C.; Klausner, Richard D.; Harford, Joe B.

doi:10.1002/j.1460-2075.1989.tb08544.x

Cited by 324 publications

(205 citation statements)

References 30 publications

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“…With an increase ferritin level and expanded LIP in the cell, TfR levels would be expected to decline in CS liver, because IRP binding to TfR mRNA is decreased, and TfR mRNA becomes unstable. 49,55 In this study, we did not detect any change in relative expression of TfR mRNA. Our results suggest that although other parameters of iron metabolism are changing during CS, the relative expression of TfR mRNA in the liver remains unchanged at 6 and 24 hours of CS.…”

Section: Discussioncontrasting

confidence: 53%

Deregulation of iron homeostasis and cold-preservation injury to rat liver stored in University of Wisconsin solution

Wyllie¹

2003

Liver Transplantation

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Very little is known about iron metabolism and the mediators of iron metabolism in liver subjected to cold storage before transplantation. Therefore, in this study, we investigated the effect of cold storage on iron homeostasis in the rat liver. When livers were stored at 4°C in University of Wisconsin solution for up to 6 and 24 hours, significant increases occurred in the labile iron pool, ferritin protein, and heme oxygenase activity. Significant decreases in heme content and iron regulatory protein 1 and 2 binding activities occurred by 24 hours. Liver injury indicated by significant increases in University of Wisconsin solution transaminase activity and liver lipid hydroperoxide levels occurred by 6 and 24 hours. Taken together, these results suggest that during pretransplantation cold storage of the liver, an aberrant iron homeostasis develops that contributes to preservation injury, and predisposes the liver to reperfusion injury by iron-dependent reactive oxygen species/Fenton reaction. (Liver Transpl 2003;9:401-410.)

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Section: Discussioncontrasting

confidence: 53%

Deregulation of iron homeostasis and cold-preservation injury to rat liver stored in University of Wisconsin solution

Wyllie¹

2003

Liver Transplantation

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“…In contrast, without significant change in serum EPO level and the rHuEPO dosage in our study, a significant decrease in serum TfR concentrations paralleled a concomitant rise in TSAT within 7 d after starting IVAA medication, before any noticeable change in HCT level. The present findings are consistent with our hypothesis that an increase in cytosolic nonstorage iron induced by IVAA medication would then facilitate TfR downregulation through the IRP mechanism (8,17,18).…”

Section: Discussionsupporting

confidence: 92%

“…In the states of iron abundance, cytoplasmic IRP has aconitase activity and does not bind to iron-responsive elements, producing increased TfR mRNA degradation (18). Therefore, in contrast to the deprivation of intracellular iron, an increase of labile iron in the cytosol will result in inhibition of TfR expression.…”

mentioning

confidence: 99%

Effect of Intravenous Ascorbic Acid Medication on Serum Levels of Soluble Transferrin Receptor in Hemodialysis Patients

Tarng

Hung

Huang

2004

Journal of the American Society of Nephrology

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Abstract. Intravenous ascorbic acid (IVAA) medication has been shown to facilitate iron release from inert depots and subsequently circumvent the defective iron utilization in chronic hemodialysis (HD) patients who are treated with recombinant human erythropoietin (rHuEPO). This study focuses on the effects of IVAA supplementation on serum concentrations of soluble transferrin receptors (TfR) on the basis of the hypothesis that an increase of labile iron in the cytosol will lead to inhibition of TfR expression. First, 138 HD patients were studied to evaluate the interrelation between serum TfR and iron status. In a stepwise multivariate analysis, serum EPO and transferrin saturation (TSAT) were the two independent predictors for serum TfR in HD patients (r 2 ϭ 0.510, P Ͻ 0.001). Further analyses showed that the lower the serum EPO and the higher the TSAT, the lower the serum TfR in HD patients who are on maintenance rHuEPO treatment. Second, 36 HD patients were recruited in a randomized, controlled study to receive IVAA (total dose of 2000 mg) or normal saline (placebo) medication. Serum levels of TfR, EPO, and ferritin and TSAT were measured at baseline and within 7 d after starting IVAA or placebo. There were no significant changes in serum EPO and ferritin levels in patients who received either IVAA (n ϭ 18) or placebo (n ϭ 18). Serum TfR levels (P Ͻ 0.001) significantly declined with a parallel rise in TSAT (P Ͻ 0.05) as compared with presupplemental values within 7 d in IVAA patients before any apparent alteration in hematocrit values, but the changes were not observed in the placebo group. The trend of decreased serum TfR and increased TSAT was similar in IVAA patients with ferritin of Ͻ500 g/L or Ͼ500 g/L. It is concluded that ascorbic acid status can significantly decrease serum TfR concentrations and increase percentage of TSAT, probably through alterations in intracellular iron metabolism.

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“…On the other hand, SNPs that do not affect RNA consensus and protein sequences have not been analyzed in detail. It is conceivable that such SNPs could also lead to phenotypic effects, most likely through non-consensus-dependent mechanisms.A growing body of evidence shows that the folding of mRNA influences a diverse range of biological events such as mRNA splicing (8, 9) and processing (10-12), and translational control (13-16) and regulation (17)(18)(19). Because the structure of mRNA is determined by its nucleotide sequence and its environment, we were interested in examining whether the folding of mRNA could be influenced by the presence of SNPs.…”

mentioning

confidence: 99%

Single-nucleotide polymorphisms can cause different structural folds of mRNA

Shen¹,

Basilion

Stanton

1999

Proc. Natl. Acad. Sci. U.S.A.

286

176

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Single-nucleotide polymorphisms (SNPs) are the most common type of genetic variation in man. Genes containing one or more SNPs can give rise to two or more allelic forms of mRNAs. These mRNA variants may possess different biological functions as a result of differences in primary or higher order structures that interact with other cellular components. Here we report the observation of marked differences in mRNA secondary structure associated with SNPs in the coding regions of two human mRNAs: alanyl tRNA synthetase and replication protein A, 70-kDa subunit (RPA70). Enzymatic probing of SNP-containing allelic fragments of the mRNAs revealed pronounced allelic differences in cleavage pattern at sites 14 or 18 nt away from the SNP, suggesting that a single-nucleotide variation can give rise to different mRNA folds. By using phosphorothioate oligodeoxyribonucleotides complementary to the region of different allelic structures in the RPA70 mRNA, but not extending to the SNP itself, we find that the SNP exerts an allele-specific effect on the accessibility of its f lanking site in the endogenous human RPA70 mRNA. This further supports the allelespecific structural features identified by enzymatic probing. These results demonstrate the contribution of common genetic variation to structural diversity of mRNA and suggest a broader role than previously thought for the effects of SNPs on mRNA structure and, ultimately, biological function.Single-nucleotide polymorphisms (SNPs) are single base-pair substitutions that occur within and outside genes (1-3). SNPs account for many well characterized human phenotypes, including disease susceptibility and resistance (4, 5) and drug response (6, 7). As a result, SNP discovery efforts have markedly expanded over the past 2 years. The frequency of SNPs varies between genomic regions and between coding and noncoding sequences. The extent of nucleotide diversity ranges from 0.0003 to 0.005; in other words, there are from 3 to 50 SNPs per 10 kilobases when two chromosomes are compared (for review, see ref.2).Genes containing one or more SNPs can give rise to two or more allelic forms of mRNAs. mRNAs containing different bases at SNP sites may vary in their interactions with cellular components involved in mRNA synthesis, maturation, transport, translation, or degradation. It has been documented that a number of single base-pair substitutions alter or create essential sequence elements for splicing, processing, or translation of human mRNA (1). These SNPs are associated with altered length and/or steady-state level of cytoplasmic mRNA. On the other hand, SNPs that do not affect RNA consensus and protein sequences have not been analyzed in detail. It is conceivable that such SNPs could also lead to phenotypic effects, most likely through non-consensus-dependent mechanisms.A growing body of evidence shows that the folding of mRNA influences a diverse range of biological events such as mRNA splicing (8, 9) and processing (10-12), and translational control (13-16) and regulation (17)...

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Iron regulation of transferrin receptor mRNA levels requires iron-responsive elements and a rapid turnover determinant in the 3′ untranslated region of the mRNA.

Abstract: Post-transcriptional regulation of transferrin receptor mRNA levels by iron is mediated by a portion of the 3' untranslated region (UTR) of the mRNA. We

Cited by 324 publications

References 30 publications

Deregulation of iron homeostasis and cold-preservation injury to rat liver stored in University of Wisconsin solution

Deregulation of iron homeostasis and cold-preservation injury to rat liver stored in University of Wisconsin solution

Effect of Intravenous Ascorbic Acid Medication on Serum Levels of Soluble Transferrin Receptor in Hemodialysis Patients

Single-nucleotide polymorphisms can cause different structural folds of mRNA

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