Translational regulation of ferritin synthesis by iron.
This review starts with a description of certain features of mammalian ferritins and their DNA and RNA structures relevant to translational control of ferritin synthesis. Although the amino acid sequences of the two ferritin subunits (H and L) diverge in about 50% of the coding region, their five alpha-helices and the exon sizes of their genes are compatible with the proposition that they diverged from a single ancestral gene. Of particular note is their long 5'-untranslated regions (5'UTRs) which include a 28-nucleotide sequence almost completely identical in the H- and L-subunits of a range of species. This motif near the cap region of the 5'-UTR, which forms a specific stem-loop structure, provides for regulation of the translation of H- and L-ferritin mRNAs. When intracellular levels of chelatable iron are not in excess, a large reserve of H- and L-mRNAs is present in the cell sap, restrained from translation by a protein with an Mr of about 90-100,000 which binds to the stem-loop structure. When excess iron floods the cytosol, this protein/RNA complex appears to dissociate and the 40S ribosome subunit is now able to initiate ferritin protein synthesis so that the dormant mRNAs become active and are transferred to the polyribosomes. The mechanism whereby the binding protein is regulated in response to iron is currently under investigation. The regulatory protein occurs in the cell sap and is present in several interchangeable forms which appear to differ in the redox state of specific sulphydryls within the protein. Under some circumstances, the abundance of these forms appears to be altered by intracellular iron status. It is unclear how iron influences binding of the regulatory protein to ferritin mRNA. Some investigators consider that iron binds in the form of heme to the regulatory protein, for which they offer in vitro evidence. We have examined the role of heme versus inorganic chelatable iron in the regulation of ferritin and heme oxygenase synthesis in rat fibroblasts and hepatoma cells. By manipulating the flow of iron between the intracellular chelatable iron and heme iron pools we have concluded that chelatable iron can act as a regulator of ferritin synthesis in a manner which is independent of heme formation. This conclusion does not exclude a role for heme in some specialized cell types.
Eisenstein
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RS
United States Department of Agriculture, Human Nutrition Research Center on Aging at Tufts, Boston, Mass.
Munro
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HN
D000818:Animals; D001483:Base Sequence; D016384:Consensus Sequence; D003676:Deferoxamine / Q000494:pharmacology; D005293:Ferritins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D006418:Heme / Q000494:pharmacology; D006427:Hemin / Q000494:pharmacology; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D008954:Models, Biological; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid
D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D006418:Heme; D006427:Hemin; D005293:Ferritins; D007501:Iron; D003676:Deferoxamine