MRNA transferrin-receptor

STABILITY/TURNOVER ELEMENT (Transferrin Receptor mRNAs, 3 UTR)... 

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. 

An examination of the nucleotide sequence of transferrin-receptor mRNA reveals the presence of several IRE-like... 

Under low-iron conditions, IRE-BP binds to these IREs. However, given the location of these binding sites, the transferrin-receptor mRNA can still be translated. What happens when the iron level increases and the IRE-BP no longer binds transferrin-receptor mRNA Freed from the IRE-BP, transferrin-receptor mRNA is rapidly degraded. Thus, an increase in the cellular iron level leads to the destruction of transferrin-receptor mRNA and, hence, a reduction in the production of transferrin-receptor protein. 

Figure 31.39. Transferrin-receptor mRNA. This mRNA has a set of ironresponse elements (IREs) in its 3 untranslated region. The binding of the IRE-binding protein to these elements stabilizes the mRNA but does not interfere with translation.

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. 

Regulation of transferrin receptor mRNA stability by intracellular iron concentrations and conversion of cytoplasmic aconitase to an IRE-BP. 

Cytoplasmic aconitase binding results in an increase in the steady-state level of transferrin receptor mRNA, and subsequently TfR protein. Once the intracellular levels of iron return to normal, IRE binding activity of cytoplasmic aconitase is inactivated and TfR mRNA is rapidly degraded. 

Steady-state levels of RNA can be controlled by balancing rates of synthesis and degradation. Both endoribonucleases and exoribonucleases play a role in RNA degradation pathways. Control of transferrin-receptor mRNA levels by cytoplasmic aconitase/IRE-BP activities is a classic example of regulation of RNA turnover rates in response to physiological signals. 

Binder R, Horowitz J. A., Basilion J. P., Koeller D. M., Klausner R. D., Harford J. B. (1994) Evidence that the pathway of transferrin receptor mRNA degradation involves an endonucleolytic cleavage within the 30 UTR and does not involve poly(A) tail shortening. EMBO J 13 1969. 

Figure 8-2 Posttranscriptional regulation by IRE/IRP interactions. In iron-replete cells, IRPs do not bind to IREs. Iron starvation induces IRPs to bind to their ligands, resulting in stabilization of transferrin receptor mRNA and translational inhibition of the mRNAs encoding ferritin H- and L-chain), eALAS and mitochondrial aconitase.

An example of the role of mRNA degradation in control of translation is provided by the transferrin receptor mRNA (Eig. 16.24) The transferrin receptor is a... 

Fig. 16.24. Regulation of degradation of the mRNA for the transferrin receptor. Degradation of the mRNA is prevented by binding of the iron response element binding protein (IRE-BP) to iron response elements (IRE), which are hairpin loops located at the 3 -end of the transferrin receptor mRNA. When iron levels are high, IRE-BP binds iron and is not bound to the mRNA. The mRNA is rapidly degraded, preventing synthesis of the transferrin receptor.

Regulation of transcription by iron. A cell s ability to acquire and store iron is a carefully controlled process. Iron obtained from the diet is absorbed in the intestine and released into the circulation, where it is bound by transferrin, the iron transport protein in plasma. When a cell requires iron, the plasma iron-transferrin complex binds to the transferrin receptor in the cell membrane and is internalized into the cell. Once the iron is freed from transferrin, it then binds to ferritin, which is the cellular storage protein for iron. Ferritin has the capacity to store up to 4,000 molecules of iron per ferritin molecule. Both transcriptional and translational controls work to maintain intracellular levels of iron (see Figs. 16.23 and 16.24). When iron levels are low, the iron response element binding protein (IRE-BP) binds to specific looped structures on both the ferritin and transferrin receptor mRNAs. This binding event stabilizes the transferrin receptor mRNA so that it can be translated and the number of transferrin receptors in the cell membrane increased. Consequently, cells will take up more iron, even when plasma transferrin/iron levels are low. The binding of IRE-BP to the ferritin mRNA, however, blocks translation of the mRNA. With low levels of intracellular iron, there is little iron to store and less need for intracellular ferritin. Thus, the IRE-BP can stabilize one mRNA, and block translation from a different mRNA. 

What happens when iron levels rise Iron will bind to the IRE-BP, thereby decreasing its affinity for mRNA. When the IRE-BP dissociates from the transferrin receptor mRNA, the mRNA becomes destabilized and is degraded, leading to less receptor being synthesized. Conversely, dissociation of the IRE-BP from the ferritin mRNA allows that mRNA to be translated, thereby increasing intracellular levels of ferritin and increasing the cells capacity for iron storage. 

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. 

Zheng and Zhao (2001) reported a significant increase in the expression of transferrin receptor mRNA and a corresponding increase in cellular Fe net uptake by PC12 phaeochromocytoma cells, but not by murine astrocytes, after Mn (200 pM) exposure for 3 days. 

Formation of a site-specific mRNA-protein complex is involved in the translational control of the biosynthesis of ferritin, an iron storage protein, which is stimulated in response to the presence of iron. In this instance, a cytoplasmic repressor protein of 85 kDa binds to a highly conserved 28-nucleotide stem-loop structure in the 5 untranslated region of ferritin mRNAs in the absence of iron. In the presence of iron, the protein dissociates from the mRNA, which is then available for translation. A similar loop motif occurs in the 3 untranslated region of transferrin receptor mRNA, which is also subject to translational control by an iron-responsive repressor. 

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. 

In the next section we will outline briefly how IRPs control intracellular iron homeostasis by modulating ferritin mRNA translation and transferrin receptor mRNA stability [53,54]. 

Iron-responsive Elements and Transferrin receptor mRNA Stability. 

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