Translational Regulation of Ferritin Synthesis by Iron

Abstract

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 a-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 M(r) 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.

Dynamic Proteomics Emphasizes the Importance of Selective mRNA Translation and Protein Turnover during Arabidopsis Seed Germination

“…Therefore, FER1 and FER2 are probably involved in both free iron and ROS homeostasis during seed germination. Interestingly, ferritins were described as classic examples of translationally regulated genes (77).…”

BACH1 Is a Specific Repressor of HMOX1 That Is Inactivated by Arsenite

“…Opening of the porphyrin ring releases CO, biliverdin, and iron. Bilirubin, the reduced product of biliverdin, has anti-oxidant properties (15,46), whereas iron rapidly induces ferritin synthesis (47), which sequesters and oxidizes free iron. Thus, in addition to lowering levels of pro-oxidant heme molecule, increased HMOX1 activity results in the formation of reaction end products that have Genes that were significantly (p Ͻ 0.01) induced by both siRNA constructs are presented in the top section, whereas genes significantly (p Ͻ 0.001) induced by one siRNA but not the other are presented in the lower section.…”

Negative Control of the Poly(A)-binding Protein mRNA Translation Is Mediated by the Adenine-rich Region of Its 5′-Untranslated Region

“…For instance, feedback control of ribosomal protein L10 synthesis by the level of free L10 protein is mediated by its binding to the 5Ј-UTR of the L10 mRNA (21,22). Similarly, synthesis of ferritin is regulated in vertebrates by the iron level (23). The inhibition of ferritin mRNA translation requires the binding of a 98-kDa translation repressor polypeptide to the conserved 25-nucleotide-long sequence of its 5Ј-UTR (24,25).…”