Ferritin synthesis

Ferritin, an iron-binding protein, prevents ionized iron (Fe ) from reaching toxic levels within cells. Elemental iron stimulates ferritin synthesis by causing the release of a cytoplasmic protein that binds to a specific region in the 5 nontranslated region of ferritin mRNA. Disruption of this protein-mRNA interaction activates ferritin mRNA and results in its translation. This mechanism provides for rapid control of the synthesis of a protein that sequesters Fe +, a potentially toxic molecule. 

In 1976, Hamish Munro proposed a model for the translational control of ferritin synthesis (Zahringer et al., 1976), which not only represents a crucial and remarkably far-sighted contribution to our understanding of cellular iron metabolism, but also in the more general context of the posttranscriptional control of gene expression. 

The early work of Fineberg and Greenberg 128) as well as that of Drysdale and Monroe 129) indicate that oral or intramuscular administration of iron enhances the rate of ferritin synthesis in the intestinal mucosa as well as other tissue. Drysdale and Monroe foimd little effect of actinomycin, an inhibitor of RNA synthesis, on iron-induced ferritin synthesis and suggested that the apoferritin was stabilized by being bound to the iron core. Recently Yoshino et al. 130) using higher concentrations of actinomycin were able to inhibit markedly the induced synthesis of ferritin. The mechanism for iron induction of ferritin is certainly not clear at this time. 

A rapid translational response of ferritin has been reported to occur after ferritin mRNA was recruited to polysomes [14]. An increase in the cytosolic ferritin mRNA and ferritin protein following ischemia and reperfiision of the intestine was also reported [26]. Reperfusion has been shown to cause ferritin degradation, followed by activation of ferritin synthesis [27,28]. 

This communication has reconfirmed the marked protection against myocardial reperfiision injury afforded by ischemic PC. The novel findings in this communication are that following prolonged ischemia, PC causes a marked decrease of the levels of cellular redistribution and extra-cellular mobilization of iron and copper. Furthermore, PC is associated with an accumulation of intracellular ferritin, and a concomitant decrease in ferritin-iron saturation. It is postulated that the low, but significant and reproducible, mobilization levels of intracellular iron, following each cycle of PC, have led to the conversion of the iron-responsive proteins, notably IRP-1, to cytosolic aconitase, and the consequent relief of the tight inhibitory control of ferritin synthesis. 

Ferritin synthesis is primarily regulated at the post-transcriptional level [42-44], through a rapid translational response to influx of free iron [14], allowing the detection of changes in ferritin content shortly after stimulation. The changes in tissue ferritin content may therefore reflect the participation of this protein in the modulations of free iron in cardiac tissue following ischemia and reperfusion with or without PC. 

Tacchini, L. Recalcati, S. Bemelli-Zazzera, A. Cairo, G. Induction of ferritin synthesis in ischemic-reperfiised rat liver analysis of the molecular mechanisms. Gastroenterology. 113 946-953 1997. 

Cairo, G. Tacchini, L. Pogliaghi, G. Anzon, E. Tomasi, A. Bemelli-Zazzera, A. Induction of ferritin synthesis by oxidative stress. Transcriptional and post-transcriptional regulation by expansion of the free iron pool. J. Biol. Chem. 270 700-703 1995. 

The levels of transferrin receptor and ferritin are regulated in a coordinated manner. When a cell needs more iron, the transferrin receptor increases in number in the plasma membrane of the cell, thus promoting uptake of Fe. At the same time, ferritin synthesis decreases, promoting the use of iron by Fe-requiring proteins in the cell. The levels of transferritin and ferritin are controlled by changes in the mRNA coding for these proteins, as detailed later in this section. 

Smith KR, Aust AE (1997) Mobilization of iron from urban particulates leads to generation of reactive oxygen species in vitro and induction of ferritin synthesis in human lung epithehal cells. Chem Res Toxicol 10 828-834... 

Rogers JT, Bridges KR, Durmowicz GP, Glass J, Auron PE, Munro HN. Translational control during the acute phase response. Ferritin synthesis in response to interleukin-1. J Biol Chem 1990 265 14572-8. 

IRE, unoccupied, allowing polyeoma formation and increased ferritin synthesis... 

During low levels of intracellular chelatable iron, iron storage declines due to inhibition of ferritin synthesis cellular entry of iron increases due to enhanced transferrin receptor synthesis. An opposing set of events occurs... 

This model has a number of attractive features. Not only is it compatible with the fact that Fe3+ is the preferred form of iron under physiological conditions, where the rate of autoxidation of Fea+ to insoluble hydroxide under mildly oxidising conditions is extremely rapid but it could also account for the stimulation of ferritin synthesis by iron at the level of translation of a stable wRNA (Section X), since it seems reasonable to assume that, whereas the apoferritin monomer shows no tendency to dissociate under physiological conditions (Section VIB), the molecule is presumably synthesised as apoferritin subunits, which could then associate around performed micellar cores. 

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