c-Myc represses and Miz-1 activates the murine natural resistance-associated protein 1 promoter.
Iron is essential for growth, and impaired iron homoeostasis through a non-conserved mutation within murine Nramp1, 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 the Nramp1 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 Nramp1 promoter. 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 for Nramp1.
Bowen
Holly
H
Biochemistry and Molecular Biology, University of Southampton, Bassett Crescent East, United Kingdom.
Biggs
Thelma E
TE
Phillips
Emma
E
Baker
Stephen T
ST
Perry
V Hugh
VH
Mann
Derek A
DA
Barton
C Howard
CH
D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology; D019556:COS Cells; D027682:Cation Transport Proteins / Q000235:genetics*; D002455:Cell Division; D002460:Cell Line; D002999:Clone Cells; D004247:DNA; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology; D000099173:Natural Resistance-associated Macrophage Protein 1
D027682:Cation Transport Proteins; D004247:DNA; D004268:DNA-Binding Proteins; D016271:Proto-Oncogene Proteins c-myc; D000099173:Natural Resistance-associated Macrophage Protein 1