Translation of ferritin light and heavy subunit mRNAs is regulated by intracellular chelatable iron levels in rat hepatoma cells.
Acute administration of iron to rats has been previously shown to induce liver ferritin synthesis by increasing the translation of inactive cytoplasmic ferritin mRNAs for both heavy (H) and light (L) subunits by mobilizing them onto polyribosomes. In this report rat hepatoma cells in culture are used to explore the relationship of this response to intracellular iron levels. After adding iron as ferric ammonium citrate to the medium, latent ferritin H- and L-mRNAs were extensively transferred to polyribosomes, accompanied by increased uptake of [35S]methionine into ferritin protein. Because total cellular levels of L- and H-mRNA were not significantly changed by exposure to iron, the increased ferritin mRNAs on polyribosomes most probably come from an inactive cytoplasmic pool, consistent with the inability of actinomycin-D and of cordycepin to inhibit iron-induced ferritin synthesis. When deferoxamine mesylate, an intracellular iron chelator, was added after the addition of iron to the medium, ferritin mRNA on the polyribosomes was reduced, while the free messenger pool increased, and ferritin synthesis diminished. In contrast, the extracellular iron chelator diethylenetriaminepentaacetic acid failed to inhibit the induction of ferritin protein synthesis. Addition of iron in the form of hemin also caused translocation of mRNA to polyribosomes, a response that could be similarly quenched by deferoxamine. Because hemin does not release chelatable iron extracellularly, we conclude that the level of chelatable iron within the cell has a regulatory role in ferritin synthesis through redistribution of the messenger RNAs between the free mRNA pool and the polyribosomes.
Rogers
J
J
Munro
H
H
D000818:Animals; D002460:Cell Line; D004247:DNA / Q000032:analysis; D003609:Dactinomycin / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology*; D005293:Ferritins / Q000235:genetics*; D006418:Heme / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology* / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D046911:Macromolecular Substances; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics* / Q000302:isolation & purification; D051381:Rats
D046911:Macromolecular Substances; D012333:RNA, Messenger; D003609:Dactinomycin; D006418:Heme; D004247:DNA; D005293:Ferritins; D007501:Iron; D003676:Deferoxamine