Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The iron regulatory element (IRE) in the 5'-untranslated region of ferritin mRNA interacts with a specific regulator protein (P-90, IRE-BP, or FRP) to block translation. High cellular iron changes the IRE/P-90 interaction to relax the translational block and allow polyribosome formation. We now show that the IRE and base-paired flanking regions also enhance translation in the absence of P-90, explaining the high translational efficiency of deregulated ferritin mRNA observed previously. The effect of the IRE on translational efficiency was examined by comparing four sets of mRNAs: (1) +/- IRE in animal (frog) ferritin, regulated translationally by iron in vivo; (2) +/- animal IRE fused with plant (soybean) ferritin, regulated transcriptionally by iron in vivo; (3) repositioned IRE in animal ferritin; (4) mutated IRE in animal ferritin with G16A substitution, which decreases P-90 binding (negative control). The IRE region increased translational efficiency of both the animal ferritin and the heterologous IRE/soybean ferritin fusion mRNAs; the effect was observed in cell-free translation systems from either plants (wheat germ) or animals (rabbit reticulocyte). Repositioning the IRE further from the 5' cap eliminated positive control of translation. The single base mutation had no effect, indicating that positive and negative translational control involves different sections of the IRE region. Thus, the IRE region in ferritin mRNA encodes both positive translational control and, when combined with the regulator protein P-90, negative translational control.
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PMID:The iron regulatory region of ferritin mRNA is also a positive control element for iron-independent translation. 154 22

Ferritin and transferrin receptors are co-ordinately regulated by the same RNA-protein interaction: the conserved iron regulatory element (IRE) in mRNA and the IRE-binding protein (IRE-BP/IRP/FRP/P-90). The 28 nucleotide IRE in ferritin mRNA is a single copy, with base-paired flanking regions (FL), located near the 5' cap. In the transferrin receptor mRNA, the IRE is located in the 3' untranslated region, as five variable copies and lacking predicted base-paired flanking regions; an alternate predicted structure without IREs has similar stability. When iron is scarce, ferritin mRNA does not form polyribosomes whereas the transferrin receptor mRNA is translated; when iron is abundant, ferritin mRNA forms polyribosomes and the transferrin receptor mRNA is degraded. To investigate structures which contribute to differences in the regulation of the two mRNAs, the effect of mutation of the ferritin FL was studied. Changes in structure (changes in reactivity with RNase V1 and RNase S1. Fe-bleomycin) and changes in function (translation in rabbit reticulocyte extracts) were compared for mutant and wild-type FL sequences in ferritin mRNA. The disruption of a triplet of base-pairs in the FL had diminished regulation; a second mutation to restore the triplet base-pairs conferred wild-type translational regulation. Conformation of the mutant RNA-IRE-BP complex was also different. We show that the triplet of base-pairs is conserved; the triplet is also the location of IRE-BP-dependent conformational changes in the FL structure previously observed. Increasing FL base-pairs had no effect on function. Structural changes associated with altered function included bleomycin sites in the IRE, suggesting an alternate conformation of the hairpin, and different base-stacking (V1 sensitivity) in the FL. The function of the FL, which is altered by mutation of phylogenetically conserved triplet base-pairs, may be enhancement of formation of a particular IRE stem-loop-protein interaction.
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PMID:The influence of the base-paired flanking region on structure and function of the ferritin mRNA iron regulatory element. 768 92