Effects of the Ferritin Open Reading Frame on Translational Induction by iron

Abstract

Publisher Summary Ferritin—a multimeric iron-storage protein—is evolutionarily conserved from prokaryotes to eukaryotes. It has been proposed that ferritin acts both to store iron for later use and to defend the cytosol against the generation of potentially toxic free radicals via Fenton oxygen chemistry. The regulation of ferritin synthesis is tightly coupled to changes in intracellular iron concentrations in both cultured cells and model vertebrate organisms. Cells in vertebrate organisms respond to excess iron chiefly by post-transcriptional mechanisms. Factors that modulate the effect of iron on ferritin expression are cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), nitric oxide (NO), and oxidative agents. Cytokines such as IL-1β modulate the expression of ferritin in the presence of iron. The regulation is accomplished both by transcriptional and translational mechanisms. There have been numerous reports demonstrating that the effect of ferritin iron-responsive element (IRE) on the iron inducibility of heterologous open reading frames is not as potent as on that of endogenous ferritin mRNAs. The difference in inducibility is accounted for by sequences downstream from the IRE and probably within the ferritin open reading frame (ORF). However, mRNAs that contain the ferritin ORF but lack IRE have little or no iron inducibility. This indicates a requirement for iron-responsive protein (IRP) to bind the IRE, and this interaction serves as the fundamental iron-responsive component of the translational regulatory system for ferritin.