Identification of a novel iron-responsive element in murine and human erythroid delta-aminolevulinic acid synthase mRNA.

Dandekar, Thomas; Stripecke, Renata; Gray, Nicola K.; Goossen, B; Constable, Anne; Johansson, Hans; Hentze, Matthias W.

doi:10.1002/j.1460-2075.1991.tb07716.x

Cited by 338 publications

(186 citation statements)

References 46 publications

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“…A search for a putative IRE was performed for Ferl and Fer2. The criteria of an IRE, as defined by Dandekar et al (1991) and Klausner et al (1993), are the presence of a sixmembered loop S'CAGUGN 3', a proximal stem of five paired bases, followed by an unpaired cytosine six nucleotides 5' of the loop and a bottom stem. Interestingly, no such IRE was found in the 5'UTRs of Ferl and Fed.…”

Section: Resultsmentioning

confidence: 99%

Ferritin mRNAs in Schistosoma Mansoni do not have Iron‐Responsive Elements for Post‐Transcriptional Regulation

Schüssler

Pötters

Winnen

et al. 1996

European Journal of Biochemistry

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Schistosomu mansoni possesses two isoforms of ferritin, soma and yolk ferritin. The soma ferritin occurs at a low level in most cells of both genders, whereas the yolk ferritin is a female-specific gene product that is expressed at high level in the vitellarium. In higher animals, ferritin mRNA is regulated by iron via the interaction of cytoplasmic binding proteins (IRPs) with a specific sequence element in the 5' untranslated region (UTR) referred to as the iron-responsive element (IRE). Sequence studies of the 5' UTRs, gel retardation assays, and hybridization experiments show that neither ferritin mRNAs of S. rnansoni is regulated by an IRE/IRP mechanism. It is suggested that ferritins in schistosomes are controlled only at the transcriptional level.

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Section: Resultsmentioning

confidence: 99%

Ferritin mRNAs in Schistosoma Mansoni do not have Iron‐Responsive Elements for Post‐Transcriptional Regulation

Schüssler

Pötters

Winnen

et al. 1996

European Journal of Biochemistry

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“…Physiologically, such a situation occurs when genetic diseases such as sickle cell disease are treated with regular blood transfusions, leading to iron overload and saturation of available ferritin with iron (17); excess iron then has to be removed by cumbersome chelation therapies. Because only Ϸ50% of the ferritin mRNA is activated (29,30), a strategy for increasing ferritin synthesis is finding a small molecule that binds to the ferritin IRE, blocks or alters binding of the IRP, and allows translation of the ferritin mRNA (3). A challenge in such a strategy is identifying a small molecule that selectively interacts with the ferritin IRE compared to mRNA with other IRE isoforms, such as the transferrin receptor (TfR) IRE.…”

mentioning

confidence: 99%

The up-regulation of ferritin expression using a small-molecule ligand to the native mRNA

Tibodeau

Fox²,

Ropp³

et al. 2005

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

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The binding of small molecules to distinctive three-dimensional structures in mRNA provides a new dimension in RNA control, previously limited to the targeting of secondary structures with antisense and RNA interference; such targeting can modulate mRNA function and rates of protein biosynthesis. Small molecules that selectively bind the iron-responsive element (IRE), a specific three-dimensional structure in the noncoding region of the ferritin mRNA model that is recognized by the iron-regulatory protein repressor, were identified by using chemical footprinting. The assay used involved an oxoruthenium(IV) complex that oxidizes guanine bases in RNA sequences. Small molecules that blocked oxidation of guanines in the internal loop region were expected to selectively increase the rate of ferritin synthesis, because the internal loop region of the ferritin IRE is distinctive from those of other IREs. The natural product yohimbine was found (based on gel mobility shifts) to block cleavage of the internal loop RNA site by >50% and seemed to inhibit protein binding. In the presence of yohimbine, the rate of biosynthesis of ferritin in a cell-free expression system (rabbit reticulocyte lysate) increased by 40%. Assignment of the IRE-yohimbine interaction as the origin of this effect was supported by a similar increase in synthesis of luciferase protein in a chimera of the IRE and luciferase gene. The identification of a small, drug-like molecule that recognizes a naturally occurring three-dimensional mRNA structure and regulates protein biosynthesis rates raises the possibility that small molecules can regulate protein biosynthesis by selectively binding to mRNA.footprinting ͉ protein synthesis ͉ RNA structure ͉ RNA-binding drugs ͉ gene expression T he targeting of small molecules to three-dimensional structures in RNA has the potential to change the synthesis rate of the encoded proteins (1-4); an example is alteration of the control of reverse-transcription rate rates of HIV-1 RNA by trans-activation responsive region RNA, a target of many druglike molecules (5-9). A principal challenge in targeting mRNA is identifying three-dimensional RNA structures that are functionally relevant and exhibit structures amenable to selective binding in the presence of large quantities of other nucleic acids (5-7). Recent findings on the activation of bacterial riboswitches by metabolites provide incentive to pursue mRNA binding as a new avenue for pharmaceutical research (10), particularly given the intriguing possibility that such elements exist in eukaryotes (11,12). The advantages of using drug-like molecules to target three-dimensional RNA targets include the ability to escape biological systems that respond to targeting helical RNA structures (13), the ability to identify potentially useful RNA targets in genome sequences (14,15), and the possibility of synthesizing reasonably large quantities of RNA for screening by chemical methods (2,16). An additional appeal is that chemicalfootprinting techniques, which are currently more ...

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“…The iron-induced decrease in IRP-1 binding activity occurs through a switch between apoprotein (high affinity) and [4Fe-4S] forms (low affinity) without changes in IRP-1 levels (18), whereas the decrease in IRP-2 binding activity is due to iron-induced IRP-2 proteolysis (19,20). IREs are also present on the 5Ј-untranslated regions of erythroid 5-aminolevulinate synthase (21) and mitochondrial aconitase (22) and on mitochondrial succinate dehydrogenase subunit b in Drosophila melanogaster (23). In addition to iron, nitric oxide (24 -26), oxidative stress (27,28), and ascorbic acid (29) have also been shown to regulate IRP binding to the IREs (reviewed in Ref.…”

mentioning

confidence: 99%

Resistance to the Antitumor Agent Gallium Nitrate in Human Leukemic Cells Is Associated with Decreased Gallium/Iron Uptake, Increased Activity of Iron Regulatory Protein-1, and Decreased Ferritin Production

Chitambar

Wereley

1997

Journal of Biological Chemistry

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The mechanism of drug resistance to gallium nitrate is not known. Since gallium can be incorporated into ferritin, an iron storage protein that protects cells from iron toxicity, we investigated whether ferritin expression was altered in gallium-resistant (R) CCRF-CEM cells. We found that the ferritin content of R cells was decreased, while heavy chain ferritin mRNA levels and iron regulatory protein-1 (IRP-1) RNA binding activity were increased. IRP-1 protein levels were similar in gallium-sensitive (S) and R cells, indicating that R cells contain a greater proportion of IRP-1 in a high affinity mRNA binding state. 59 Fe uptake and transferrin receptor expression were decreased in R cells. In both S and R cells, gallium inhibited cellular 59 Fe uptake, increased ferritin mRNA and protein, and decreased IRP-1 binding activity. Gallium uptake by R cells was markedly diminished; however, the sensitivity of R cells to gallium could be restored by increasing their uptake of gallium with excess transferrin. Our results suggest that R cells have developed resistance to gallium by down-regulating their uptake of gallium. In parallel, iron uptake by R cells is also decreased, leading to changes in iron homeostasis. Furthermore, since gallium has divergent effects on iron uptake and ferritin synthesis, its action may also include a direct effect on ferritin mRNA induction and IRP-1 activity.Gallium nitrate, a group IIIa metal salt with antineoplastic activity (1), is currently undergoing evaluation as a chemotherapeutic agent. A number of clinical studies have shown gallium to be effective in the treatment of lymphoma and bladder cancer (2-4). Although gallium is in clinical use, information regarding its action at the cellular and molecular levels is largely incomplete. It has been known for some time that gallium resembles iron in certain respects. Gallium binds avidly to the iron transport protein Tf 1 (5) and is incorporated into cells by Tf receptor-dependent and -independent transport systems (6 -8). Furthermore, we have shown that gallium inhibits the growth of several leukemic cell lines by inhibiting cellular iron uptake and by blocking the activity of ribonucleotide reductase (9 -11).Iron taken up by cells is stored in ferritin, a high molecular weight protein composed of 24 subunits of H and L chains (12). Ferritin sequesters excess intracellular iron and protects cells from the toxicity of iron overload. An increase in the delivery of iron to cells therefore serves as a powerful stimulus for ferritin synthesis. It is now established that iron-dependent ferritin and transferrin receptor gene expression is regulated by the binding of two iron regulatory proteins (IRPs), IRP-1 and IRP-2, to sequences termed iron-responsive elements (IREs) present at the 5Ј-untranslated region of ferritin mRNA and the 3Ј-untranslated region of Tf receptor mRNA (13-17). In irondepleted cells, IRPs bind with high affinity to the IREs, resulting in suppression of ferritin mRNA translation and stabilization of Tf receptor mRNA (incr...

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Identification of a novel iron-responsive element in murine and human erythroid delta-aminolevulinic acid synthase mRNA.

Cited by 338 publications

References 46 publications

Ferritin mRNAs in Schistosoma Mansoni do not have Iron‐Responsive Elements for Post‐Transcriptional Regulation

Ferritin mRNAs in Schistosoma Mansoni do not have Iron‐Responsive Elements for Post‐Transcriptional Regulation

The up-regulation of ferritin expression using a small-molecule ligand to the native mRNA

Resistance to the Antitumor Agent Gallium Nitrate in Human Leukemic Cells Is Associated with Decreased Gallium/Iron Uptake, Increased Activity of Iron Regulatory Protein-1, and Decreased Ferritin Production

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