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

c-Myc represses and Miz-1 activates the murine natural resistance-associated protein 1 promoter
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.
0021-9258
34997-35006
Bowen, H.
4ed2a24f-bf81-4d60-b475-567f9ad321bb
Biggs, T.E.
5ef9af49-c9ba-44ed-b9b1-2aacdc5bee2d
Phillips, E.
16ee48e2-0cca-478b-b233-28aca3957406
Baker, S.T.
359e3325-2545-44e5-a64d-8d4a433d8af7
Perry, V.H.
8f29d36a-8e1f-4082-8700-09483bbaeae4
Mann, D.A.
54e772bb-f94f-4485-98c8-b2339a929d86
Barton, C.H.
5dfb4e1a-d559-4b58-9036-31de1e6c9ad8
Bowen, H.
4ed2a24f-bf81-4d60-b475-567f9ad321bb
Biggs, T.E.
5ef9af49-c9ba-44ed-b9b1-2aacdc5bee2d
Phillips, E.
16ee48e2-0cca-478b-b233-28aca3957406
Baker, S.T.
359e3325-2545-44e5-a64d-8d4a433d8af7
Perry, V.H.
8f29d36a-8e1f-4082-8700-09483bbaeae4
Mann, D.A.
54e772bb-f94f-4485-98c8-b2339a929d86
Barton, C.H.
5dfb4e1a-d559-4b58-9036-31de1e6c9ad8

Bowen, H., Biggs, T.E., Phillips, E., Baker, S.T., Perry, V.H., Mann, D.A. and Barton, C.H. (2002) c-Myc represses and Miz-1 activates the murine natural resistance-associated protein 1 promoter. The Journal of Biological Chemistry, 277 (38), 34997-35006. (doi:10.1074/jbc.M204232200).

Record type: Article

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.

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Published date: 2002

Identifiers

Local EPrints ID: 26956
URI: http://eprints.soton.ac.uk/id/eprint/26956
ISSN: 0021-9258
PURE UUID: 3dd59e68-27ff-4a53-b7e4-601913eb5045

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Date deposited: 27 Apr 2006
Last modified: 15 Jul 2019 19:13

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