Ferritin mRNA and

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. 

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]. 

Coordinate translational regulation of ferritin mRNA and transferrin receptor mRNA in nonerythroid cells. Iron regulatory proteins (IRP) are RNA-binding proteins that bind to iron regulatory elements (IREs). IREs are hairpin structures with loops consisting of CAGUGN sequences and are located at the 5 -untranslated region (UTR) and 3 -UTR for ferritin mRNA and transferrin mRNA, respectively. 

Two well characterized internal loops that serve as protein recognition elements in an RNA mediated regulation are the Iron Responsive Element, IRE, found in the 5 -untranslated region (UTR) of ferritin mRNA and the 3 UTR of transferrin receptor mRNA and the Rev Response Element, RRE, found in the env gene of the HIV-1 retrovirus. These RNA elements are the binding sites of the IRP and Rev proteins respectively. 

Ferritin synthesis is stimulated by available iron. In the absence of Fe , the apo- form of an iron-binding protein binds to ferritin mRNA and blocks its translation (Caughman et al. 1988 Dix et al. 1992 Leibold and Guo 1992). However, with excessive iron the maximal rate of translation... 

Lessons from the genetic control of translation of ferritin mRNAS and transferrin receptor mRNA stability can be applied to the control of APP expression by iron. This information will be relevant to Alzheimer s disease pathology after applying these models of post-transcriptional control to APP gene expression. 

Synthesis of the transferrin receptor (TfR) and that of ferritin are reciprocally linked to cellular iron content. Specific untranslated sequences of the mRNAs for both proteins (named iron response elements) interact with a cytosolic protein sensitive to variations in levels of cellular iron (iron-responsive element-binding protein). When iron levels are high, cells use stored ferritin mRNA to synthesize ferritin, and the TfR mRNA is degraded. In contrast, when iron levels are low, the TfR mRNA is stabilized and increased synthesis of receptors occurs, while ferritin mRNA is apparently stored in an inactive form. This is an important example of control of expression of proteins at the translational level. 

Figure 7.4 (a) IREs in eukaryotic mRNAs the secondary structures of ferritin and transferrin receptor IREs. (b) The IRE localization in mRNAs the translation/ribosome binding element in the 5 -UTR of ferritin mRNA is above, that of the stability/ turnover element in the 3 -UTR of transferrin receptor mRNA is below. Adapted from Theil, 1998, by courtesy of Marcel Dekker, Inc. 

Figure 8.15 IRE in ferritin mRNA from Crichton (2001) and outline of translational regulation of mRNAs of a number of proteins involved in iron metabolism in low and high iron. (From Wallander et al., 2006. Copyright 2006, with permission from Elsevier.)...

As mentioned above, there are the profound relationships between Al and Fe metabolism in mammalian cells Al can bind proteins bound to Fe. Apo-Tf binds to Al to form di-Al-Tf (Al2Tf). Al2Tf is recognized by TfR to be taken up by brain cells. Al binds Fe storage protein, ferritin and also influences the expression of ferritin mRNA. If this is a reliable phenomenon, Al is required to interact with IRPs which post-trascriptionally regulate the expression of ferritin or TfR mRNAs. 

Thomson AM, Rogers IT, Leedman PJ. Iron-regulatory proteins, iron-responsive elements and ferritin mRNA translation. Int. J. Biochem. Cell. Biol. 1999 31 1139-1152. 

Consider ferritin first. Ferritin mRNA includes a stem-loop structure termed an iron-response element (IRE) in its 5 untranslated region (Figure 31.38). This stem-loop binds a 90-kd protein, czAlsd m IRE-bindingprotein (IRE-BP), that blocks the initiation of translation. When the iron level increases, the IRE-BP binds iron as a 4Fe-4S cluster. The IRE-BP bound to iron cannot bind RNA, because the binding sites for iron and RNA substantially overlap. Thus, in the presence of iron, ferritin mRNA is released from the IRE-BP and translated to produce ferritin, which sequesters the excess iron. 

It is proposed that during the PC phase small, but significant, levels of intracellular iron undergo re-distribution and mobilization. This, in turn, produces the necessary signal for enhanced translation of ferritin mRNA, increasing its level and its capacity to scavenge and store iron. 

The structure of the IRE that occurs in the sequence of ferritin mRNA appears in Figure 10.34. The iron response element is a small region of RNA, and it is distinguished in that it spontaneously folds upon itself to form a hairpin shape. The ribonucleotides of RNA follow similar base-pairing rules as in DNA. In RNA, guanine binds to cytosine, and adenine binds to uracil. It is accurate to state that within the hairpin the RNA occurs as double-stranded RNA. To repeal, one might note that DNA contains a sequence of DNA bases that is used to code for the iron response clement, but these DNA bases do not bind the IRF... 

Toth, I., and Bridget, K. R. (1995). Ascrobic acid enhances ferritin mRNA translation by an IRP/aconit0se switch. /. Bioi Citem. 270, 19540-19544. 

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