Identification of the Iron-Responsive Element for the Translational Regulation of Human Ferritin mRNA

Abstract

Regulated translation of messenger RNA offers an important mechanism for the control of gene expression. The biosynthesis of the intracellular iron storage protein ferritin is translationally regulated by iron. A cis-acting element that is both necessary and sufficient for this translational regulation is present within the 5' nontranslated leader region of the human ferritin H-chain messenger RNA. In this report the iron-responsive element (IRE) was identified by deletional analysis. Moreover, a synthetic oligodeoxynucleotide was shown to be able to transfer iron regulation to a construct that would otherwise not be able to respond to iron. The IRE has been highly conserved and predates the evolutionary segregation between amphibians, birds, and man. The IRE may prove to be useful for the design of translationally regulated expression systems.

Structure and organization of the gene encoding a mouse mitochondrial stress‐70 protein

“…Computer-aided analysis of this sequence demonstrates a stable secondary structure, as described above. Other genes for TGF-b1 [31], TGF-B3 [32], ferritin [33,34], and c-.&platelet-derived growth factor 2 [35,36] have been reported to contain the similar sequence with the stable secondary structure in the S-untranslated region, which acts as a translation regulator [37,38]. Thus, further experiments are required to elucidate the regulatory mechanism of expression of the PBP741CSA gene.…”

Mutational analysis of the [4Fe-4S]-cluster converting iron regulatory factor from its RNA-binding form to cytoplasmic aconitase.

“…IREs are present in several mRNA species coding for key proteins in iron metabolism. Ferritin H-and L-chain (Aziz and Munro, 1987;Hentze et al, 1987), erythroid 5-aminolevulinic acid synthase (May et al, 1990;Cox et al, 1991;Dandekar et al, 1991) and mitochondrial aconitase mRNAs (Dandekar et al, 1991;Zheng et al, 1992b) all carry an IRE in their 5' untranslated region (UTR) and are inhibited in translation by the binding of IRF (Walden et al, 1989;Goossen et al, 1990;Bhasker et al, 1993;Melefors et al, 1993). In contrast, transferrin receptor mRNA, which contains five highly related IREs in its 3' UTR (Casey et al, 1988), is stabilized by the IRE-IRF interaction, and therefore receptor synthesis is enhanced (Miilner and Kuhn, 1988;Muillner et al, 1989).…”

Cytoplasmic Protein mRNA Interaction Mediates cGMP-modulated Translational Control of the Asialoglycoprotein Receptor

“…Analysis of the cis-acting mRNA sequences led to the definition of the iron-responsive element with a putative stem-loop structure in the 5Ј-UTR (30). Modeling of the ASGR H2b 5Ј-UTR indicated the presence of two potential regions of secondary structure.…”

“…Perhaps the best-defined example of translational regulation is that of ferritin synthesis in iron-deficient cells (16,30). Analysis of the cis-acting mRNA sequences led to the definition of the iron-responsive element with a putative stem-loop structure in the 5Ј-UTR (30).…”

“…To establish the cap site status of ASGR mRNA in cells grown in FBS as compared with dFBS and dFBS supplemented with 500 M cGMP, the extent of cap-dependent in vitro translation was determined. Total mRNA was isolated from HuH-7 cells (5 ϫ 10 7 ) and translated in a rabbit reticulocyte lysate in the presence or absence of m 7 GpppG, an inhibitor of cap-dependent initiation (30). The labeled ASGR translation product was recovered by immunoprecipitation using a polyclonal antibody to affinity-purified human receptor.…”