Control of Transferrin Receptor Expression via Nitric Oxide-mediated Modulation of Iron-regulatory Protein 2

Cellular iron storage and uptake are coordinately regulated post-transcriptionally by cytoplasmic factors, iron-regulatory proteins 1 and 2 (IRP-1 and IRP-2). When iron in the intracellular transit pool is scarce, IRPs bind to iron-responsive elements (IREs) in the 5′-untranslated region of the ferritin mRNA and 3′-untranslated region of the transferrin receptor (TfR) mRNA. Such binding inhibits translation of ferritin mRNA and stabilizes the mRNA for TfR, whereas the opposite scenario develops when iron in the transit pool is plentiful. However, we (Richardson, D. R., Neumannova, V., Nagy, E., and Ponka, P. (1995) Blood 86, 3211–3219) and others reported that the binding of IRPs to IREs can also be modulated by nitric oxide (NO). In this study, we showed that a short exposure of RAW 264.7 cells (a murine macrophage cell line) to the NO+ donor, sodium nitroprusside (SNP), caused a significant decrease in IRP-2 binding to the IREs followed by IRP-2 degradation and that these changes occurred without affecting IRP-1 binding. The SNP-mediated degradation of IRP-2 in RAW 264.7 cells could be prevented by MG-132 or lactacystin, known inhibitors of proteasome-dependent protein degradation. A SNP-mediated decrease in IRP-2 binding and levels was associated with a dramatic decrease in TfR mRNA levels and an increase in ferritin synthesis. Importantly, the proteasome inhibitor MG-132 prevented the SNP-mediated decrease in TfR mRNA levels. These observations suggest that IRP-2 can play an important role in controlling transferrin receptor expression. Cellular iron storage and uptake are coordinately regulated post-transcriptionally by cytoplasmic factors, iron-regulatory proteins 1 and 2 (IRP-1 and IRP-2). When iron in the intracellular transit pool is scarce, IRPs bind to iron-responsive elements (IREs) in the 5′-untranslated region of the ferritin mRNA and 3′-untranslated region of the transferrin receptor (TfR) mRNA. Such binding inhibits translation of ferritin mRNA and stabilizes the mRNA for TfR, whereas the opposite scenario develops when iron in the transit pool is plentiful. However, we (Richardson, D. R., Neumannova, V., Nagy, E., and Ponka, P. (1995) Blood 86, 3211–3219) and others reported that the binding of IRPs to IREs can also be modulated by nitric oxide (NO). In this study, we showed that a short exposure of RAW 264.7 cells (a murine macrophage cell line) to the NO+ donor, sodium nitroprusside (SNP), caused a significant decrease in IRP-2 binding to the IREs followed by IRP-2 degradation and that these changes occurred without affecting IRP-1 binding. The SNP-mediated degradation of IRP-2 in RAW 264.7 cells could be prevented by MG-132 or lactacystin, known inhibitors of proteasome-dependent protein degradation. A SNP-mediated decrease in IRP-2 binding and levels was associated with a dramatic decrease in TfR mRNA levels and an increase in ferritin synthesis. Importantly, the proteasome inhibitor MG-132 prevented the SNP-mediated decrease in TfR mRNA levels. These observations suggest that IRP-2 can play an important role in controlling transferrin receptor expression. transferrin transferrin receptor iron-responsive element untranslated region iron-regulatory protein sodium nitroprusside S-nitroso-N-acetyl-penicillamine lipopolysaccharide interferon labile iron pool Iron is essential for all living organisms and is involved in cell proliferation, respiration, oxygen and electron transport, and DNA synthesis (1Klausner R.D. Rouault T.A. Harford J.B. Cell. 1993; 72: 19-28Abstract Full Text PDF PubMed Scopus (1046) PubMed Scopus PubMed Scopus P. PubMed Scopus P. However, iron is to of iron with that can to the of the can and organisms to in the iron and the cells iron storage the of cells in the iron a transferrin Iron uptake the binding of to the of an by and the of iron by a decrease in iron iron the by and the intracellular labile iron that the for the synthesis of and proteins is ferritin P. PubMed Scopus P. proteins 1 and 2 (IRP-1 and are cytoplasmic proteins known to with iron-responsive elements are in the 3′-untranslated region of TfR mRNA (1Klausner R.D. Rouault T.A. Harford J.B. Cell. 1993; 72: 19-28Abstract Full Text PDF PubMed Scopus (1046) PubMed Scopus Cell. Full Text PDF PubMed Scopus the of for ferritin (1Klausner R.D. Rouault T.A. Harford J.B. Cell. 1993; 72: 19-28Abstract Full Text PDF PubMed Scopus (1046) PubMed Scopus PubMed Scopus Scopus and PubMed Scopus When iron the IRP-1 is the binding The binding of IRPs to the in the of the ferritin mRNA the translation of an of IRPs with IREs in the of TfR mRNA stabilizes the the the of the labile iron pool IRP-1 and to degradation of in an translation of ferritin mRNA and degradation of TfR mRNA in R.D. Rouault T.A. Harford J.B. Cell. 1993; 72: 19-28Abstract Full Text PDF PubMed Scopus (1046) PubMed Scopus PubMed Scopus P. PubMed Scopus is and PubMed Scopus an of the and in cells IRP-1 also D. Harford J.B. Rouault T.A. R.D. PubMed Scopus D. Rouault T.A. Harford J.B. R.D. PubMed Importantly, of are in the and D. Rouault T.A. R.D. 1993; Full Text PDF PubMed T.A. Harford J.B. R.D. Cell. Full Text PDF PubMed Scopus that are involved in the binding of iron in the PubMed Scopus The and binding of IRP-1 are The IRP-1 with an in cells and binding the in IRP-1 the and binding in PubMed Scopus and P. PubMed Scopus by and and a of and cells T.A. Harford J.B. R.D. PubMed Scopus 1993; Full Text PDF PubMed Full Text PDF PubMed Full Text Full Text PDF PubMed Scopus IRP-2 with IRP-1 in a a in region a that is for the protein for degradation the when iron levels are R.D. Rouault T.A. PubMed Scopus Full Text Full Text PDF PubMed Scopus IRP-2 an and oxide is an important of are binding to iron in the of or in the of important iron proteins PubMed Scopus P. PubMed Scopus P. Scopus Iron with NO+ of of proteins PubMed Scopus PubMed Scopus Cell. Full Text PDF PubMed Scopus is known to the of in PubMed Scopus and P. Scopus to we showed that IRP-1 binding TfR and TfR NO+ IRP-1 TfR and binding in cells P. PubMed P. PubMed that of cells with the NO+ of the binding of IRP-1 to the a known to TfR mRNA degradation. the with the that be followed by of the in an increase in the binding of IRP-1 to a known to TfR this study, we RAW 264.7 cells and that of and in opposite IRP-1 binding we that IRP-2 be a important and for that of NO+ IRP-1 could be IRP-2 binding and protein levels in RAW 264.7 cells to the NO+ degradation of IRP-2 could be prevented by MG-132 or lactacystin, that IRP-2 degradation the a decrease in IRP-2 a short exposure to the NO+ was associated with a dramatic decrease in TfR mRNA levels that occurred IRP-1 binding was that IRP-2 an important role in controlling TfR is to without be of in (1Klausner R.D. Rouault T.A. Harford J.B. Cell. 1993; 72: 19-28Abstract Full Text PDF PubMed Scopus (1046) P. PubMed Scopus organisms to of the of to the and in of the essential element for the synthesis of and The of iron in the intracellular labile iron pool is is known that iron in this and pool can be by organisms are with that coordinately iron uptake and storage and iron in the levels. The of iron in the is by are for of ferritin and TfR expression. When iron in the is scarce, binding to the IREs ferritin mRNA translation and TfR mRNA and the opposite scenario develops when iron in the transit pool is (1Klausner R.D. Rouault T.A. Harford J.B. Cell. 1993; 72: 19-28Abstract Full Text PDF PubMed Scopus (1046) PubMed Scopus PubMed Scopus P. PubMed Scopus P. iron is the that can and can be by of and PubMed Scopus IRP-1 is to an protein is modulated by PubMed Scopus P. Scopus that can IRP-1 binding P. PubMed 1993; PubMed Scopus and D. 1993; PubMed Scopus in PubMed Scopus in an increase in TfR mRNA levels. However, is can the of or iron in the and PubMed Scopus the and that the of IRP-1 is to the of also IRP-1 with In this study, we that can IRP-1 in RAW 264.7 cells 1 and is in suggest that binding of IRP-1 by with and this is also by of Full Text Full Text PDF PubMed Scopus is IRP-1 and this in is caused by a a element in the of IRP-2 T.A. Harford J.B. R.D. PubMed Scopus 1993; Full Text PDF PubMed Full Text PDF PubMed The that the in IRP-1 are in IRP-2 Full Text Full Text PDF PubMed Scopus IRP-2 is in cells 1993; Full Text PDF PubMed Full Text PDF PubMed R.D. Rouault T.A. PubMed Scopus Full Text Full Text PDF PubMed Scopus R.D. R.D. Rouault T.A. PubMed Scopus and the is and to IRP-2 to degradation in R.D. Rouault T.A. PubMed Scopus In this study, we that a exposure of RAW 264.7 cells to the NO+ in a significant decrease in IRP-2 binding to the and this binding was also that IRP-2 protein levels in RAW 264.7 this decrease occurred the of IRP-2 binding 2 the degradation of IRP-2 is to the protein synthesis inhibitor that protein synthesis is for the of the SNP-mediated of and degradation of IRP-2 in RAW 264.7 cells could be prevented by MG-132 or known proteasome inhibitors Cell. Full Text PDF PubMed Scopus D. Cell. Full Text PDF PubMed Scopus PubMed Scopus is of to that the IRP-2 protein can be in the of IRP-2 binding and is that the of IRP-2 binding the protein is the of IRP-2 degradation the we the that this be involved in IRP-2 degradation in RAW 264.7 is an iron be that of cells with could to the of iron and in IRP-2 degradation. However, to decrease IRP-2 protein levels when iron to the cell could the decrease in IRP-2 levels. the of the iron or to the decrease in IRP-2 protein levels that the of was to iron to the also the that NO+ could increase iron levels in the this NO+ decrease IRP-1 iron levels in the In this is important to that of IRP-1 and IRP-2 with Full Text Full Text PDF PubMed Scopus we that can NO+ is to and P. Ponka, that NO+ is to intracellular iron levels iron the with the suggest that in cells of IRP-2 and that this this protein for degradation the is that the to IRP-2 is for degradation of this the involved are that IRP-2 a for R.D. R.D. Rouault T.A. PubMed Scopus and for degradation. Importantly, when of in the of IRP-2 are the degradation of this protein is R.D. Rouault T.A. PubMed Scopus that these play a role in controlling IRP-2 degradation. with the NO+ donor, we that of in the of IRP-2 is a that this protein for and degradation. of RAW 264.7 cells with and a dramatic decrease in IRP-2 and levels in TfR mRNA levels and these changes are to in RAW 264.7 that in and RAW 264.7 cells of IRP-2 levels are known to increase in PubMed Scopus that to are of of proteins PubMed Scopus P. PubMed are IRP-2 is in RAW 264.7 cells with NO+ or and this study, we also that a decrease in IRP-2 binding and a short exposure of RAW 264.7 cells to was associated with a dramatic decrease in TfR mRNA levels 2 and Importantly, these changes occurred the when binding of IRP-1 was by the of this is the that the decrease in TfR mRNA levels with a decrease in IRP-2 binding and IRP-1 for binding to that TfR the of in a cell IRP-2 PubMed Scopus this in that in the of IRP-1 is to TfR mRNA levels. IRP-2 a role in controlling TfR mRNA levels. IRP-1 is in involved in the of TfR, and for this is by the in 2 and These that the of IRP-1 in cells is associated with an increase in TfR mRNA is that are also involved in the of TfR P. PubMed Scopus is that can TfR mRNA decrease in RAW 264.7 the proteasome inhibitor MG-132 prevented the SNP-mediated decrease in TfR mRNA that the decrease is to IRP-2 degradation. we cells with of the IREs D. PubMed Scopus that of these cells with TfR mRNA levels without affecting TfR for the of the in the of also ferritin mRNA levels in RAW 264.7 cells without or with that ferritin mRNA levels when ferritin synthesis These suggest that ferritin synthesis is that iron uptake and storage are coordinately regulated a the by IRP-1 and to that the of IRPs iron levels in the and the of this pool controlling TfR and ferritin However, iron to be regulated by iron also by that a associated with P. PubMed and others 1993; PubMed Scopus and D. 1993; PubMed Scopus in PubMed Scopus that can iron with observations by that of the of is an important of that of RAW 264.7 cells with NO+ in a decrease in of followed by IRP-2 in The decrease in IRP-2 is associated with the decrease in TfR mRNA and changes in RAW 264.7 cells with and is to that the decrease in TfR in be in iron uptake the Iron is essential for all living organisms and is involved in cell proliferation, respiration, oxygen and electron transport, and DNA synthesis (1Klausner R.D. Rouault T.A. Harford J.B. Cell. 1993; 72: 19-28Abstract Full Text PDF PubMed Scopus (1046) PubMed Scopus PubMed Scopus P. PubMed Scopus P. However, iron is to of iron with that can to the of the can and organisms to in the iron and the cells iron storage the of cells in the iron a transferrin Iron uptake the binding of to the of an by and the of iron by a decrease in iron iron the by and the intracellular labile iron that the for the synthesis of and proteins is ferritin P. PubMed Scopus P. proteins 1 and 2 (IRP-1 and are cytoplasmic proteins known to with iron-responsive elements are in the 3′-untranslated region of TfR mRNA (1Klausner R.D. Rouault T.A. Harford J.B. Cell. 1993; 72: 19-28Abstract Full Text PDF PubMed Scopus (1046) PubMed Scopus Cell. Full Text PDF PubMed Scopus the of for ferritin (1Klausner R.D. Rouault T.A. Harford J.B. Cell. 1993; 72: 19-28Abstract Full Text PDF PubMed Scopus (1046) PubMed Scopus PubMed Scopus Scopus and PubMed Scopus When iron the IRP-1 is the binding The binding of IRPs to the in the of the ferritin mRNA the translation of an of IRPs with IREs in the of TfR mRNA stabilizes the the the of the labile iron pool IRP-1 and to degradation of in an translation of ferritin mRNA and degradation of TfR mRNA in R.D. Rouault T.A. Harford J.B. Cell. 1993; 72: 19-28Abstract Full Text PDF PubMed Scopus (1046) PubMed Scopus PubMed Scopus P. PubMed Scopus IRP-1 is and PubMed Scopus an of the and in cells IRP-1 also D. Harford J.B. Rouault T.A. R.D. PubMed Scopus D. Rouault T.A. Harford J.B. R.D. PubMed Importantly, of are in the and D. Rouault T.A. R.D. 1993; Full Text PDF PubMed T.A. Harford J.B. R.D. Cell. Full Text PDF PubMed Scopus that are involved in the binding of iron in the PubMed Scopus The and binding of IRP-1 are The IRP-1 with an in cells and binding the in IRP-1 the and binding in PubMed Scopus and P. PubMed Scopus A by and and a of and cells T.A. Harford J.B. R.D. PubMed Scopus 1993; Full Text PDF PubMed Full Text PDF PubMed Full Text Full Text PDF PubMed Scopus IRP-2 with IRP-1 in a a in region a that is for the protein for degradation the when iron levels are R.D. Rouault T.A. PubMed Scopus Full Text Full Text PDF PubMed Scopus IRP-2 an and oxide is an important of are binding to iron in the of or in the of important iron proteins PubMed Scopus P. PubMed Scopus P. Scopus Iron with NO+ of of proteins PubMed Scopus PubMed Scopus Cell. Full Text PDF PubMed Scopus is known to the of in PubMed Scopus and P. Scopus to we showed that IRP-1 binding TfR and TfR NO+ IRP-1 TfR and binding in cells P. PubMed P. PubMed that of cells with the NO+ of the binding of IRP-1 to the a known to TfR mRNA degradation. the with the that be followed by of the in an increase in the binding of IRP-1 to a known to TfR mRNA. In this study, we RAW 264.7 cells and that of and in opposite IRP-1 binding we that IRP-2 be a important and for that of NO+ IRP-1 could be IRP-2 binding and protein levels in RAW 264.7 cells to the NO+ degradation of IRP-2 could be prevented by MG-132 or lactacystin, that IRP-2 degradation the a decrease in IRP-2 a short exposure to the NO+ was associated with a dramatic decrease in TfR mRNA levels that occurred IRP-1 binding was that IRP-2 an important role in controlling TfR expression. is to without be of in (1Klausner R.D. Rouault T.A. Harford J.B. Cell. 1993; 72: 19-28Abstract Full Text PDF PubMed Scopus (1046) P. PubMed Scopus organisms to of the of to the and in of the essential element for the synthesis of and The of iron in the intracellular labile iron pool is is known that iron in this and pool can be by organisms are with that coordinately iron uptake and storage and iron in the levels. The of iron in the is by are for of ferritin and TfR expression. When iron in the is scarce, binding to the IREs ferritin mRNA translation and TfR mRNA and the opposite scenario develops when iron in the transit pool is (1Klausner R.D. Rouault T.A. Harford J.B. Cell. 1993; 72: 19-28Abstract Full Text PDF PubMed Scopus (1046) PubMed Scopus PubMed Scopus P. PubMed Scopus P. iron is the that can and can be by of and PubMed Scopus IRP-1 is to an protein is modulated by PubMed Scopus P. Scopus that can IRP-1 binding P. PubMed 1993; PubMed Scopus and D. 1993; PubMed Scopus in PubMed Scopus in an increase in TfR mRNA levels. However, is can the of or iron in the and PubMed Scopus the and that the of IRP-1 is to the of also IRP-1 with In this study, we that can IRP-1 in RAW 264.7 cells 1 and is in suggest that binding of IRP-1 by with and this is also by of Full Text Full Text PDF PubMed Scopus is IRP-1 and this in is caused by a a element in the of IRP-2 T.A. Harford J.B. R.D. PubMed Scopus 1993; Full Text PDF PubMed Full Text PDF PubMed The that the in IRP-1 are in IRP-2 Full Text Full Text PDF PubMed Scopus IRP-2 is in cells 1993; Full Text PDF PubMed Full Text PDF PubMed R.D. Rouault T.A. PubMed Scopus Full Text Full Text PDF PubMed Scopus R.D. R.D. Rouault T.A. PubMed Scopus and the is and to IRP-2 to degradation in R.D. Rouault T.A. PubMed Scopus In this study, we that a exposure of RAW 264.7 cells to the NO+ in a significant decrease in IRP-2 binding to the and this binding was also that IRP-2 protein levels in RAW 264.7 this decrease occurred the of IRP-2 binding 2 the degradation of IRP-2 is to the protein synthesis inhibitor that protein synthesis is for the of the SNP-mediated of and degradation of IRP-2 in RAW 264.7 cells could be prevented by MG-132 or known proteasome inhibitors Cell. Full Text PDF PubMed Scopus D. Cell. Full Text PDF PubMed Scopus PubMed Scopus is of to that the IRP-2 protein can be in the of IRP-2 binding and is that the of IRP-2 binding the protein is the of IRP-2 degradation the we the that this be involved in IRP-2 degradation in RAW 264.7 is an iron be that of cells with could to the of iron and in IRP-2 degradation. However, to decrease IRP-2 protein levels when iron to the cell could the decrease in IRP-2 levels. the of the iron or to the decrease in IRP-2 protein levels that the of was to iron to the also the that NO+ could increase iron levels in the this NO+ decrease IRP-1 iron levels in the In this is important to that of IRP-1 and IRP-2 with Full Text Full Text PDF PubMed Scopus we that can NO+ is to and P. Ponka, that NO+ is to intracellular iron levels iron the with the suggest that in cells of IRP-2 and that this this protein for degradation the is that the to IRP-2 is for degradation of this the involved are that IRP-2 a for R.D. R.D. Rouault T.A. PubMed Scopus and for degradation. Importantly, when of in the of IRP-2 are the degradation of this protein is R.D. Rouault T.A. PubMed Scopus that these play a role in controlling IRP-2 degradation. with the NO+ donor, we that of in the of IRP-2 is a that this protein for and degradation. of RAW 264.7 cells with and a dramatic decrease in IRP-2 and levels in TfR mRNA levels and these changes are to in RAW 264.7 that in and RAW 264.7 cells of IRP-2 levels are known to increase in PubMed Scopus that to are of of proteins PubMed Scopus P. PubMed are IRP-2 is in RAW 264.7 cells with NO+ or and this study, we also that a decrease in IRP-2 binding and a short exposure of RAW 264.7 cells to was associated with a dramatic decrease in TfR mRNA levels 2 and Importantly, these changes occurred the when binding of IRP-1 was by the of this is the that the decrease in TfR mRNA levels with a decrease in IRP-2 binding and IRP-1 for binding to that TfR the of in a cell IRP-2 PubMed Scopus this in that in the of IRP-1 is to TfR mRNA levels. IRP-2 a role in controlling TfR mRNA levels. IRP-1 is in involved in the of TfR, and for this is by the in 2 and These that the of IRP-1 in cells is associated with an increase in TfR mRNA is that are also involved in the of TfR P. PubMed Scopus is that can TfR mRNA decrease in RAW 264.7 the proteasome inhibitor MG-132 prevented the SNP-mediated decrease in TfR mRNA that the decrease is to IRP-2 degradation. we cells with of the IREs D. PubMed Scopus that of these cells with TfR mRNA levels without affecting TfR for the of the in the of also ferritin mRNA levels in RAW 264.7 cells without or with that ferritin mRNA levels when ferritin synthesis These suggest that ferritin synthesis is that iron uptake and storage are coordinately regulated a the by IRP-1 and to that the of IRPs iron levels in the and the of this pool controlling TfR and ferritin However, iron to be regulated by iron also by that a associated with P. PubMed and others 1993; PubMed Scopus and D. 1993; PubMed Scopus in PubMed Scopus that can iron with observations by that of the of is an important of that of RAW 264.7 cells with NO+ in a decrease in of followed by IRP-2 in The decrease in IRP-2 is associated with the decrease in TfR mRNA and changes in RAW 264.7 cells with and is to that the decrease in TfR in be in iron uptake the Iron is to without be of in (1Klausner R.D. Rouault T.A. Harford J.B. Cell. 1993; 72: 19-28Abstract Full Text PDF PubMed Scopus (1046) P. PubMed Scopus organisms to of the of to the and in of the essential element for the synthesis of and The of iron in the intracellular labile iron pool is is known that iron in this and pool can be by organisms are with that coordinately iron uptake and storage and iron in the levels. The of iron in the is by are for of ferritin and TfR expression. When iron in the is scarce, binding to the IREs ferritin mRNA translation and TfR mRNA and the opposite scenario develops when iron in the transit pool is (1Klausner R.D. Rouault T.A. Harford J.B. Cell. 1993; 72: 19-28Abstract Full Text PDF PubMed Scopus (1046) PubMed Scopus PubMed Scopus P. PubMed Scopus P. However, iron is the that can and can be by of and PubMed Scopus IRP-1 is to an protein is modulated by PubMed Scopus P. Scopus that can IRP-1 binding P. PubMed 1993; PubMed Scopus and D. 1993; PubMed Scopus in PubMed Scopus in an increase in TfR mRNA levels. However, is can the of or iron in the and PubMed Scopus the and that the of IRP-1 is to the of also IRP-1 with In this study, we that can IRP-1 in RAW 264.7 cells 1 and is in suggest that binding of IRP-1 by with and this is also by of Full Text Full Text PDF PubMed Scopus IRP-2 is IRP-1 and this in is caused by a a element in the of IRP-2 T.A. Harford J.B. R.D. PubMed Scopus 1993; Full Text PDF PubMed Full Text PDF PubMed The that the in IRP-1 are in IRP-2 Full Text Full Text PDF PubMed Scopus IRP-2 is in cells 1993; Full Text PDF PubMed Full Text PDF PubMed R.D. Rouault T.A. PubMed Scopus Full Text Full Text PDF PubMed Scopus R.D. R.D. Rouault T.A. PubMed Scopus and the is and to IRP-2 to degradation in R.D. Rouault T.A. PubMed Scopus In this study, we that a exposure of RAW 264.7 cells to the NO+ in a significant decrease in IRP-2 binding to the and this binding was also that IRP-2 protein levels in RAW 264.7 this decrease occurred the of IRP-2 binding 2 the degradation of IRP-2 is to the protein synthesis inhibitor that protein synthesis is for the of the SNP-mediated of and degradation of IRP-2 in RAW 264.7 cells could be prevented by MG-132 or known proteasome inhibitors Cell. Full Text PDF PubMed Scopus D. Cell. Full Text PDF PubMed Scopus PubMed Scopus is of to that the IRP-2 protein can be in the of IRP-2 binding and is that the of IRP-2 binding the protein is the of IRP-2 degradation the we the that this be involved in IRP-2 degradation in RAW 264.7 is an iron be that of cells with could to the of iron and in IRP-2 degradation. However, to decrease IRP-2 protein levels when iron to the cell could the decrease in IRP-2 levels. the of the iron or to the decrease in IRP-2 protein levels that the of was to iron to the also the that NO+ could increase iron levels in the this NO+ decrease IRP-1 iron levels in the In this is important to that of IRP-1 and IRP-2 with Full Text Full Text PDF PubMed Scopus we that can NO+ is to and P. Ponka, that NO+ is to intracellular iron levels iron the with the suggest that in cells of IRP-2 and that this this protein for degradation the is that the to IRP-2 is for degradation of this the involved are that IRP-2 a for R.D. R.D. Rouault T.A. PubMed Scopus and for degradation. Importantly, when of in the of IRP-2 are the degradation of this protein is R.D. Rouault T.A. PubMed Scopus that these play a role in controlling IRP-2 degradation. with the NO+ donor, we that of in the of IRP-2 is a that this protein for and degradation. of RAW 264.7 cells with and a dramatic decrease in IRP-2 and levels in TfR mRNA levels and these changes are to in RAW 264.7 that in and RAW 264.7 cells of IRP-2 levels are known to increase in PubMed Scopus that to are of of proteins PubMed Scopus P. PubMed are IRP-2 is in RAW 264.7 cells with NO+ or and In this study, we also that a decrease in IRP-2 binding and a short exposure of RAW 264.7 cells to was associated with a dramatic decrease in TfR mRNA levels 2 and Importantly, these changes occurred the when binding of IRP-1 was by the of this is the that the decrease in TfR mRNA levels with a decrease in IRP-2 binding and IRP-1 for binding to that TfR the of in a cell IRP-2 PubMed Scopus this in that in the of IRP-1 is to TfR mRNA levels. IRP-2 a role in controlling TfR mRNA levels. IRP-1 is in involved in the of TfR, and for this is by the in 2 and These that the of IRP-1 in cells is associated with an increase in TfR mRNA levels. is that are also involved in the of TfR P. PubMed Scopus is that can TfR mRNA decrease in RAW 264.7 the proteasome inhibitor MG-132 prevented the SNP-mediated decrease in TfR mRNA that the decrease is to IRP-2 degradation. we cells with of the IREs D. PubMed Scopus that of these cells with TfR mRNA levels without affecting TfR for the of the in the of also ferritin mRNA levels in RAW 264.7 cells without or with that ferritin mRNA levels when ferritin synthesis These suggest that ferritin synthesis In is that iron uptake and storage are coordinately regulated a the by IRP-1 and to that the of IRPs iron levels in the and the of this pool controlling TfR and ferritin However, iron to be regulated by iron also by that a associated with P. PubMed and others 1993; PubMed Scopus and D. 1993; PubMed Scopus in PubMed Scopus that can iron with observations by that of the of is an important of that of RAW 264.7 cells with NO+ in a decrease in of followed by IRP-2 in The decrease in IRP-2 is associated with the decrease in TfR mRNA and changes in RAW 264.7 cells with and is to that the decrease in TfR in be in iron uptake the for with cells with TfR IREs and for for and for