c-Myc Represses and Miz-1 Activates the Murine Natural Resistance-associated Protein 1 Promoter

Abstract

Iron is essential for growth, and impaired iron homoeostasis through a non-conserved mutation within murineNramp1, also termed Slc11a1, contributes to susceptibility to infection. Nramp1 depletes the macrophage cytosol of iron, with effects on iron-regulated gene expression and iron-dependent processes. Wu and colleagues (Wu, K.-J., Polack, A., and Dalla-Favera, R. (1999) Science 283, 676–679) showed converse control of iron regulatory protein expression (IRP2) and H-ferritin by c-Myc, suggesting a role for c-Myc in enhancing cytoplasmic iron levels for growth. We investigated if c-Myc also regulates Nramp1 expression. We show an inverse correlation with cell growth, and in co-transfection experiments c-Myc represses the Nramp1 promoter. Within theNramp1 promoter we identified six non-canonical E boxes, which are not important for c-Myc repression. By deletion analysis the repressor site maps to one or more initiator elements flanking the transcriptional initiation site. Co-transfections with the c-Myc interacting zinc finger protein (Miz-1) show that Miz-1 can overcome c-Myc repression of Nramp1, and, from a deletion construct lacking E box sites, Miz-1 activates the Nramp1promoter. These studies reinforce the link between c-Myc and iron regulation and provide further evidence that c-Myc negatively regulates genes that decrease the iron content of the cytosol. The results provide further support for a divalent cation antiporter function forNramp1. Iron is essential for growth, and impaired iron homoeostasis through a non-conserved mutation within murineNramp1, also termed Slc11a1, contributes to susceptibility to infection. Nramp1 depletes the macrophage cytosol of iron, with effects on iron-regulated gene expression and iron-dependent processes. Wu and colleagues (Wu, K.-J., Polack, A., and Dalla-Favera, R. (1999) Science 283, 676–679) showed converse control of iron regulatory protein expression (IRP2) and H-ferritin by c-Myc, suggesting a role for c-Myc in enhancing cytoplasmic iron levels for growth. We investigated if c-Myc also regulates Nramp1 expression. We show an inverse correlation with cell growth, and in co-transfection experiments c-Myc represses the Nramp1 promoter. Within theNramp1 promoter we identified six non-canonical E boxes, which are not important for c-Myc repression. By deletion analysis the repressor site maps to one or more initiator elements flanking the transcriptional initiation site. Co-transfections with the c-Myc interacting zinc finger protein (Miz-1) show that Miz-1 can overcome c-Myc repression of Nramp1, and, from a deletion construct lacking E box sites, Miz-1 activates the Nramp1promoter. These studies reinforce the link between c-Myc and iron regulation and provide further evidence that c-Myc negatively regulates genes that decrease the iron content of the cytosol. The results provide further support for a divalent cation antiporter function forNramp1. A biallelic phenotype in mouse, termedIty/Lsh/Bcg, was identified in response to infection by obligate intracellular macrophage pathogens (1Plant J. Glynn A.A. Nature. 1974; 248: 345-347Crossref PubMed Scopus (95) Google Scholar, 2Bradley D.J. Nature. 1974; 250: 353-354Crossref PubMed Scopus (103) Google Scholar, 3Gros P. Skamene E. Forget A.I. J. Immunol. 1981; 127: 2417-2421PubMed Google Scholar). Nramp1 1The abbreviations used are: Nramp1 , natural resistance-associated macrophage protein 1; Slc11a1, solute carrier family 11a member 1; DCT1/DMT1, divalent cation/metal transporter 1; iNos, inducible nitric oxide synthase; IRP2, iron regulatory protein 2; LIP, labile iron pool; Inr, initiator element; Miz-1, Myc-interacting zinc finger protein 1; GST, glutathioneS-transferase; BrdUrd, bromodeoxyuridine; CAT, chloramphenicol acetyltransferase; LA, LipofectAMINE; EF, elongation factor; CMV, cytomegalovirus; eGFP, enhanced green fluorescent protein; Lamp1, lysosomal membrane-associated protein; AdML, adenovirus major late promoter; TGF, transforming growth factor. 1The abbreviations used are: Nramp1 , natural resistance-associated macrophage protein 1; Slc11a1, solute carrier family 11a member 1; DCT1/DMT1, divalent cation/metal transporter 1; iNos, inducible nitric oxide synthase; IRP2, iron regulatory protein 2; LIP, labile iron pool; Inr, initiator element; Miz-1, Myc-interacting zinc finger protein 1; GST, glutathioneS-transferase; BrdUrd, bromodeoxyuridine; CAT, chloramphenicol acetyltransferase; LA, LipofectAMINE; EF, elongation factor; CMV, cytomegalovirus; eGFP, enhanced green fluorescent protein; Lamp1, lysosomal membrane-associated protein; AdML, adenovirus major late promoter; TGF, transforming growth factor.(also termed Slc11a1) was isolated as the positional gene candidate for Ity/Lsh/Bcg (4Vidal S.M. Malo D. Vogan Skamene E. P. PubMed Scopus Google Scholar). studies the of the was identified J. PubMed Scopus Google Scholar). to infection within Nramp1 D. Vogan J. E. P. PubMed Scopus Google Scholar). The is to the of within cell of as by gene and experiments Malo D. Skamene E. P. J. PubMed Scopus Google Scholar, Skamene E. Malo D. P. Google Scholar). Malo D. Skamene E. P. J. PubMed Scopus Google Scholar). Nramp1 was the for control the of intracellular pathogens was not the a transporter function (4Vidal S.M. Malo D. Vogan Skamene E. P. PubMed Scopus Google Scholar). studies showed the Nramp1 protein was in a on intracellular late J. PubMed Scopus Google Scholar, E. P. J. PubMed Scopus Google Scholar, J. PubMed Google Scholar). Nramp1 to the of a E. P. J. PubMed Scopus Google Scholar, J. PubMed Google and a more in response to with J. PubMed Google Scholar). These to the that growth control of pathogens by the of the of the or by the of essential The of a candidate was from studies on a was isolated as an gene P. PubMed Scopus Google was by through a divalent Nature. PubMed Scopus Google Scholar). in the and the are with impaired and cell iron D. PubMed Scopus Google Scholar). on the between the P. PubMed Scopus Google Nramp1 was also to divalent or iron within and infection susceptibility through impaired divalent cation effects to Nramp1 PubMed Scopus Google by cation Nramp1 protein is within the of divalent between the cytosol and the of the to the effects PubMed Scopus Google Scholar). is levels in Skamene E. D. Google Scholar, PubMed Google Scholar, Google Scholar, D. J. PubMed Scopus Google Scholar). iron the link between expression and J. Immunol. Google that iron expression the factor. expression by of iron within the cell cytosol that is by as is the of cation evidence iron the as by of J. PubMed Scopus (103) Google and analysis of Nramp1 in P. J. PubMed Scopus Google Scholar). support of the intracellular P. J. PubMed Scopus Google Scholar, R. PubMed Scopus Google Scholar). to or the not P. J. PubMed Scopus Google Scholar). on the as J. PubMed Scopus (103) Google Scholar, P. J. PubMed Scopus Google or iron P. J. PubMed Scopus Google Scholar, R. PubMed Scopus Google Scholar). Nramp1 not depletes iron from the also is to in a to iron from the macrophage J. Immunol. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). to Nramp1 function are to the of and that of the the cytoplasmic iron levels to control or J. PubMed Scopus Google Scholar). iron-regulated are and the iron-regulated protein protein J. PubMed Scopus Google Scholar). The are with Nramp1 cytoplasmic iron and the iron important for macrophage function levels of and are and to the effects of on cell PubMed Google Scholar). and and iron the expression of Skamene E. D. Google Scholar, PubMed Google Scholar, Google Scholar, D. J. PubMed Scopus Google between the c-Myc family of and iron homoeostasis R. PubMed Scopus Google Scholar). A role for c-Myc was in cytoplasmic iron for cell with and effects on the expression of genes that or the of the in support of a link between c-Myc and iron by the expression in a of a PubMed Scopus Google Scholar). and colleagues D. J. PubMed Scopus Google iron-dependent growth of We to a role for c-Myc in the control of results that c-Myc represses Nramp1 expression by the that the transcriptional initiation site P. Malo D. P. PubMed Scopus (95) Google Scholar). Miz-1 P. J. PubMed Scopus Google regulates Nramp1 and in co-transfection experiments Miz-1 the effects of The provide an that further support to the that Nramp1 the iron within the and as a divalent cation antiporter P. J. PubMed Scopus Google we on the promoter and show of cell growth. We show that can cell are for a link between iron homoeostasis and with cell growth. A by Wu and colleagues R. PubMed Scopus Google showed c-Myc regulates the expression of genes that the of iron within the labile iron R. PubMed Scopus Google that c-Myc the for cell These to the promoter for regulation by the Nramp1 promoter we identified six E. PubMed Scopus Google we protein to site not not important for the effects of c-Myc and a c-Myc site not show transcriptional not deletion of site and flanking with an in promoter and to Miz-1 Miz-1 and colleagues P. J. PubMed Scopus Google showed of the and by Miz-1, and the construct a of E box was to a suggesting that the of E box within the promoter can with the of Miz-1 to is with the in Nramp1 promoter we on from to E box site we for the construct we was to c-Myc that E box site is not of for c-Myc repression. deletion construct a for c-Myc repression. The as a promoter that can the box in J. Scopus Google Scholar). repression for the phenotype to of as PubMed Scopus Google and not c-Myc gene repression is through the not a more analysis of the and and the regulatory the and by in the promoter J. Google Scholar). studies on the the was to function as an and expression susceptibility to as J. Google Scholar, PubMed Google Scholar). studies also that promoter contributes to susceptibility to the of a PubMed Scopus Google Scholar). the results of not the in we the of a within the of the promoter the is is on the of promoter we is We that the between and in the is The contributes to promoter We evidence for or the repressor to the that the and of on of the to and the of the experiments are the of the repressor by further deletion promoter are to the of repression by c-Myc, with c-Myc of the site the and promoter of the of Nramp1 are not with promoter with a major for the promoter in the gene is to provide PubMed Scopus Google Scholar). The major that contributes to susceptibility in is the D. Vogan J. E. P. PubMed Scopus Google and not in We not that the promoter identified the the is promoter within to iron homoeostasis and to a phenotype that a of or the The is on to the promoter on the of the or to construct the more promoter in with the in studies a phenotype of expression to in a in the is the of cation by Nramp1 J. PubMed Scopus (103) Google Scholar, P. J. PubMed Scopus Google Scholar, P. J. PubMed Scopus Google Scholar, R. PubMed Scopus Google Scholar). is to the used by the results of provide for the of cation with results J. PubMed Scopus Google that Nramp1 depletes the cytosol of divalent Nramp1 as a divalent cation antiporter P. J. PubMed Scopus Google in to that a divalent cation Nature. PubMed Scopus Google Scholar). is the of within the of the P. PubMed Scopus Google Scholar). evidence is on the that c-Myc Nramp1 and on the of Wu R. PubMed Scopus Google that c-Myc the cation within the for cell as Nramp1 to levels of iron within the cytosol and as a as P. J. PubMed Scopus Google Scholar, R. PubMed Scopus Google we that c-Myc expression and Nramp1 expression growth as we These are in to of P. J. PubMed Scopus Google a fluorescent to showed of divalent and of the by and R. PubMed Scopus Google that Nramp1 from intracellular experiments we that a major on the of divalent within a macrophage and support and of an iron role for Nramp1 J. Immunol. PubMed Scopus Google J. PubMed Scopus Google Scholar). iron role for Nramp1 the and from pathogens of essential iron for intracellular is of an between c-Myc and Nramp1 and of Nramp1 from a expression regulatory control effects of Nramp1 expression on growth to We not from Nramp1 levels of protein in the cell and are and in These and of that c-Myc to levels of iron within a cell by experiments by on Miz-1, with and identified P. J. J. J. J. PubMed Scopus Google Scholar, J. P. J. PubMed Scopus Google Scholar). is of that studies by and colleagues E. P. Google showed is a for and the between c-Myc and J. PubMed Scopus Google J. D. R. PubMed Scopus Google Scholar). experiments we are the role of Miz-1 function for Nramp1 regulation on the of P. J. J. J. J. PubMed Scopus Google Scholar, J. P. J. PubMed Scopus Google Scholar). also of to if Miz-1 effects on iron levels by genes as or which to in the of iron within the cytosol. experiments we to if Miz-1 is a major regulatory for Nramp1 within the macrophage and to Miz-1 is in experiments a of protein to a to the sites, and the for Miz-1 was by studies in expression to macrophage and within an J. Immunol. PubMed Scopus Google for control within macrophage are suggesting Miz-1 to the J. PubMed Google and to A.A. J. Scholar). A of to Miz-1 to Nramp1 Nramp1 by a a role for in also A.A. J. and an between Nramp1 and PubMed Scopus Google Scholar). the of by one that to the of Nramp1 in macrophage studies the Miz-1 on Nramp1 regulation by a of A biallelic phenotype in mouse, termedIty/Lsh/Bcg, was identified in response to infection by obligate intracellular macrophage pathogens (1Plant J. Glynn A.A. Nature. 1974; 248: 345-347Crossref PubMed Scopus (95) Google Scholar, 2Bradley D.J. Nature. 1974; 250: 353-354Crossref PubMed Scopus (103) Google Scholar, 3Gros P. Skamene E. Forget A.I. J. Immunol. 1981; 127: 2417-2421PubMed Google Scholar). Nramp1 1The abbreviations used are: Nramp1 , natural resistance-associated macrophage protein 1; Slc11a1, solute carrier family 11a member 1; DCT1/DMT1, divalent cation/metal transporter 1; iNos, inducible nitric oxide synthase; IRP2, iron regulatory protein 2; LIP, labile iron pool; Inr, initiator element; Miz-1, Myc-interacting zinc finger protein 1; GST, glutathioneS-transferase; BrdUrd, bromodeoxyuridine; CAT, chloramphenicol acetyltransferase; LA, LipofectAMINE; EF, elongation factor; CMV, cytomegalovirus; eGFP, enhanced green fluorescent protein; Lamp1, lysosomal membrane-associated protein; AdML, adenovirus major late promoter; TGF, transforming growth factor. 1The abbreviations used are: Nramp1 , natural resistance-associated macrophage protein 1; Slc11a1, solute carrier family 11a member 1; DCT1/DMT1, divalent cation/metal transporter 1; iNos, inducible nitric oxide synthase; IRP2, iron regulatory protein 2; LIP, labile iron pool; Inr, initiator element; Miz-1, Myc-interacting zinc finger protein 1; GST, glutathioneS-transferase; BrdUrd, bromodeoxyuridine; CAT, chloramphenicol acetyltransferase; LA, LipofectAMINE; EF, elongation factor; CMV, cytomegalovirus; eGFP, enhanced green fluorescent protein; Lamp1, lysosomal membrane-associated protein; AdML, adenovirus major late promoter; TGF, transforming growth factor.(also termed Slc11a1) was isolated as the positional gene candidate for Ity/Lsh/Bcg (4Vidal S.M. Malo D. Vogan Skamene E. P. PubMed Scopus Google Scholar). studies the of the was identified J. PubMed Scopus Google Scholar). to infection within Nramp1 D. Vogan J. E. P. PubMed Scopus Google Scholar). The is to the of within cell of as by gene and experiments Malo D. Skamene E. P. J. PubMed Scopus Google Scholar, Skamene E. Malo D. P. Google Scholar). Malo D. Skamene E. P. J. PubMed Scopus Google Scholar). Nramp1 was the for control the of intracellular pathogens was not the a transporter function (4Vidal S.M. Malo D. Vogan Skamene E. P. PubMed Scopus Google Scholar). studies showed the Nramp1 protein was in a on intracellular late J. PubMed Scopus Google Scholar, E. P. J. PubMed Scopus Google Scholar, J. PubMed Google Scholar). Nramp1 to the of a E. P. J. PubMed Scopus Google Scholar, J. PubMed Google and a more in response to with J. PubMed Google Scholar). These to the that growth control of pathogens by the of the of the or by the of essential The of a candidate was from studies on a was isolated as an gene P. PubMed Scopus Google was by through a divalent Nature. PubMed Scopus Google Scholar). in the and the are with impaired and cell iron D. PubMed Scopus Google Scholar). on the between the P. PubMed Scopus Google Nramp1 was also to divalent or iron within and infection susceptibility through impaired divalent cation The effects to Nramp1 PubMed Scopus Google by cation Nramp1 protein is within the of divalent between the cytosol and the of the to the effects PubMed Scopus Google Scholar). is levels in Skamene E. D. Google Scholar, PubMed Google Scholar, Google Scholar, D. J. PubMed Scopus Google Scholar). iron the link between expression and J. Immunol. Google that iron expression the factor. expression by of iron within the cell cytosol that is by as is the of cation evidence iron the as by of J. PubMed Scopus (103) Google and analysis of Nramp1 in P. J. PubMed Scopus Google Scholar). support of the intracellular P. J. PubMed Scopus Google Scholar, R. PubMed Scopus Google Scholar). to or the not P. J. PubMed Scopus Google Scholar). on the as J. PubMed Scopus (103) Google Scholar, P. J. PubMed Scopus Google or iron P. J. PubMed Scopus Google Scholar, R. PubMed Scopus Google Scholar). Nramp1 not depletes iron from the also is to in a to iron from the macrophage J. Immunol. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). to Nramp1 function are to the of and We that of the the cytoplasmic iron levels to control or J. PubMed Scopus Google Scholar). iron-regulated are and the iron-regulated protein protein J. PubMed Scopus Google Scholar). The are with Nramp1 cytoplasmic iron and the iron important for macrophage function levels of and are and to the effects of on cell PubMed Google Scholar). and and iron the expression of Skamene E. D. Google Scholar, PubMed Google Scholar, Google Scholar, D. J. PubMed Scopus Google Scholar). between the c-Myc family of and iron homoeostasis R. PubMed Scopus Google Scholar). A role for c-Myc was in cytoplasmic iron for cell with and effects on the expression of genes that or the of the in support of a link between c-Myc and iron by the expression in a of a PubMed Scopus Google Scholar). and colleagues D. J. PubMed Scopus Google iron-dependent growth of We to a role for c-Myc in the control of results that c-Myc represses Nramp1 expression by the that the transcriptional initiation site P. Malo D. P. PubMed Scopus (95) Google Scholar). Miz-1 P. J. PubMed Scopus Google regulates Nramp1 and in co-transfection experiments Miz-1 the effects of The provide an that further support to the that Nramp1 the iron within the and as a divalent cation antiporter P. J. PubMed Scopus Google Scholar). we on the promoter and show of cell growth. We show that can cell are for a link between iron homoeostasis and with cell growth. A by Wu and colleagues R. PubMed Scopus Google showed c-Myc regulates the expression of genes that the of iron within the labile iron R. PubMed Scopus Google that c-Myc the for cell These to the promoter for regulation by the Nramp1 promoter we identified six E. PubMed Scopus Google we protein to site not not important for the effects of c-Myc and a c-Myc site not show transcriptional not deletion of site and flanking with an in promoter and to Miz-1 Miz-1 and colleagues P. J. PubMed Scopus Google showed of the and by Miz-1, and the construct a of E box was to a suggesting that the of E box within the promoter can with the of Miz-1 to is with the in Nramp1 promoter we on from to E box site we for the construct we was to c-Myc that E box site is not of for c-Myc repression. deletion construct a for c-Myc repression. The as a promoter that can the box in J. Scopus Google Scholar). repression for the phenotype to of as PubMed Scopus Google and not c-Myc gene repression is through the not a more analysis of the and and the regulatory the and by in the promoter J. Google Scholar). studies on the the was to function as an and expression susceptibility to as J. Google Scholar, PubMed Google Scholar). studies also that promoter contributes to susceptibility to the of a PubMed Scopus Google Scholar). the results of not the in we the of a within the of the promoter the is is on the of promoter we is We that the between and in the is The contributes to promoter We evidence for or the repressor to the that the and of on of the to and the of the experiments are the of the repressor by further deletion promoter are to the of repression by c-Myc, with c-Myc of the site the and promoter of the of Nramp1 are not with promoter with a major for the promoter in the gene is to provide PubMed Scopus Google Scholar). The major that contributes to susceptibility in is the D. Vogan J. E. P. PubMed Scopus Google and not in We not that the promoter identified the the is promoter within to iron homoeostasis and to a phenotype that a of or the The is on to the promoter on the of the or to construct the more promoter in with the in studies a phenotype of expression to in a in the is the of cation by Nramp1 J. PubMed Scopus (103) Google Scholar, P. J. PubMed Scopus Google Scholar, P. J. PubMed Scopus Google Scholar, R. PubMed Scopus Google Scholar). is to the used by the results of provide for the of cation with results J. PubMed Scopus Google that Nramp1 depletes the cytosol of divalent Nramp1 as a divalent cation antiporter P. J. PubMed Scopus Google in to that a divalent cation Nature. PubMed Scopus Google Scholar). is the of within the of the P. PubMed Scopus Google Scholar). evidence is on the that c-Myc Nramp1 and on the of Wu R. PubMed Scopus Google that c-Myc the cation within the for cell as Nramp1 to levels of iron within the cytosol and as a as P. J. PubMed Scopus Google Scholar, R. PubMed Scopus Google we that c-Myc expression and Nramp1 expression growth as we These are in to of P. J. PubMed Scopus Google a fluorescent to showed of divalent and of the by and R. PubMed Scopus Google that Nramp1 from intracellular experiments we that a major on the of divalent within a macrophage and support and of an iron role for Nramp1 J. Immunol. PubMed Scopus Google J. PubMed Scopus Google Scholar). iron role for Nramp1 the and from pathogens of essential iron for intracellular is of an between c-Myc and Nramp1 and of Nramp1 from a expression regulatory control effects of Nramp1 expression on growth to We not from Nramp1 levels of protein in the cell and are and in These and of that c-Myc to levels of iron within a cell by experiments by on Miz-1, with and identified P. J. J. J. J. PubMed Scopus Google Scholar, J. P. J. PubMed Scopus Google Scholar). is of that studies by and colleagues E. P. Google showed is a for and the between c-Myc and J. PubMed Scopus Google J. D. R. PubMed Scopus Google Scholar). experiments we are the role of Miz-1 function for Nramp1 regulation on the of P. J. J. J. J. PubMed Scopus Google Scholar, J. P. J. PubMed Scopus Google Scholar). also of to if Miz-1 effects on iron levels by genes as or which to in the of iron within the cytosol. experiments we to if Miz-1 is a major regulatory for Nramp1 within the macrophage and to Miz-1 is in experiments a of protein to a to the sites, and the for Miz-1 was by studies in expression to macrophage and within an J. Immunol. PubMed Scopus Google for control within macrophage are suggesting Miz-1 to the J. PubMed Google and to A.A. J. Scholar). A of to Miz-1 to Nramp1 Nramp1 by a a role for in also A.A. J. and an between Nramp1 and PubMed Scopus Google Scholar). the of by one that to the of Nramp1 in macrophage studies the Miz-1 on Nramp1 regulation by a of we on the promoter and show of cell growth. We show that can cell are for a link between iron homoeostasis and with cell growth. A by Wu and colleagues R. PubMed Scopus Google showed c-Myc regulates the expression of genes that the of iron within the labile iron R. PubMed Scopus Google that c-Myc the for cell These to the promoter for regulation by the Nramp1 promoter we identified six E. PubMed Scopus Google we protein to site not not important for the effects of c-Myc and a c-Myc site not show transcriptional not deletion of site and flanking with an in promoter and to Miz-1 Miz-1 and colleagues P. J. PubMed Scopus Google showed of the and by Miz-1, and the construct a of E box was to a suggesting that the of E box within the promoter can with the of Miz-1 to is with the in Nramp1 promoter we on from to E box site we for the construct we was to c-Myc that E box site is not of for c-Myc repression. deletion construct a for c-Myc repression. The as a promoter that can the box in J. Scopus Google Scholar). repression for the phenotype to of as PubMed Scopus Google and not c-Myc gene repression is through the We not a more analysis of the and and the regulatory the and by in the promoter J. Google Scholar). studies on the the was to function as an and expression susceptibility to as J. Google Scholar, PubMed Google Scholar). studies also that promoter contributes to susceptibility to the of a PubMed Scopus Google Scholar). the results of not the in we the of a within the of the promoter the is is on the of promoter we is We that the between and in the is The contributes to promoter We evidence for or the repressor to the that the and of on of the to and the of the experiments are the of the repressor by further deletion promoter are to the of repression by c-Myc, with c-Myc of the site the and promoter of the of Nramp1 are not with promoter with a major for the promoter in the gene is to provide PubMed Scopus Google Scholar). The major that contributes to susceptibility in is the D. Vogan J. E. P. PubMed Scopus Google and not in We not that the promoter identified the the is promoter within to iron homoeostasis and to a phenotype that a of or the The is on to the promoter on the of the or to construct the more promoter in with the in studies a phenotype of expression to in a in the is the of cation by Nramp1 J. PubMed Scopus (103) Google Scholar, P. J. PubMed Scopus Google Scholar, P. J. PubMed Scopus Google Scholar, R. PubMed Scopus Google Scholar). is to the used by the results of provide for the of cation with results J. PubMed Scopus Google that Nramp1 depletes the cytosol of divalent Nramp1 as a divalent cation antiporter P. J. PubMed Scopus Google in to that a divalent cation Nature. PubMed Scopus Google Scholar). is the of within the of the P. PubMed Scopus Google Scholar). evidence is on the that c-Myc Nramp1 and on the of Wu R. PubMed Scopus Google that c-Myc the cation within the for cell as Nramp1 to levels of iron within the cytosol and as a as P. J. PubMed Scopus Google Scholar, R. PubMed Scopus Google we that c-Myc expression and Nramp1 expression growth as we These are in to of P. J. PubMed Scopus Google a fluorescent to showed of divalent and of the by and R. PubMed Scopus Google that Nramp1 from intracellular experiments we that a major on the of divalent within a macrophage and support and of an iron role for Nramp1 J. Immunol. PubMed Scopus Google J. PubMed Scopus Google Scholar). iron role for Nramp1 the and from pathogens of essential iron for intracellular growth. is of an between c-Myc and Nramp1 and of Nramp1 from a expression regulatory control effects of Nramp1 expression on growth to We not from Nramp1 levels of protein in the cell and are and in These and of that c-Myc to levels of iron within a cell by experiments by on Miz-1, with and identified P. J. J. J. J. PubMed Scopus Google Scholar, J. P. J. PubMed Scopus Google Scholar). is of that studies by and colleagues E. P. Google showed is a for and the between c-Myc and J. PubMed Scopus Google J. D. R. PubMed Scopus Google Scholar). experiments we are the role of Miz-1 function for Nramp1 regulation on the of P. J. J. J. J. PubMed Scopus Google Scholar, J. P. J. PubMed Scopus Google Scholar). also of to if Miz-1 effects on iron levels by genes as or which to in the of iron within the cytosol. experiments we to if Miz-1 is a major regulatory for Nramp1 within the macrophage and to Miz-1 is in experiments a of protein to a to the sites, and the for Miz-1 was by studies in expression to macrophage and within an J. Immunol. PubMed Scopus Google for control within macrophage are suggesting Miz-1 to the J. PubMed Google and to A.A. J. Scholar). A of to Miz-1 to Nramp1 Nramp1 by a a role for in also A.A. J. and an between Nramp1 and PubMed Scopus Google Scholar). the of by one that to the of Nramp1 in macrophage studies the Miz-1 on Nramp1 regulation by a of We are to for the Miz-1 expression