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c-Myc represses and Miz-1 activates the murine natural resistance-associated protein 1 promoter

Lookup NU author(s): Professor Derek Mann

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Abstract

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.


Publication metadata

Author(s): Mann DA; Bowen H; Biggs TE; Phillips E; Baker ST; Perry VH; Barton CH

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2002

Volume: 277

Issue: 38

Pages: 34997-5006

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology, Inc.

URL: http://dx.doi.org/10.1074/jbc.M204232200

DOI: 10.1074/jbc.M204232200

Notes: 0021-9258 (Print) Journal Article


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