Characterisation of the Solute carrier family member 11a1 (Slc11a1) Promoter: Regulation by c-Myc and Miz-1

Abstract

In mice, natural resistance to infection with several antigenically unrelated intracellular pathogens including Salmonella typhimurium, Leishmania donovani and Mycobacterium bovis, is mediated by a single gene on chromosome 1 termed S1c 11a1 (Solute carrier family 11a member1, formerly Nramp1).  S1c11a1 encodes a 548 amino acid integral membrane protein that localises to the late endocytic compartments of resting macrophages.  Infection of the macrophage with intracellular pathogens leads to targeting of S1C11a1 from endocytic vesicles to the phagosomal membrane where it alters the microenvironment of the vesicle, thereby controlling replication of the pathogen.  How S1c11a1 performs this task is the centre of much controversy.  High sequence similarity (77% protein identity) to Nramp2, a ubiquitous divalent cation symporter, and the presence of a highly conserved transport motif has led to the suggestion that S1c11a1 may also function as a divalent cation transporter, leading to a decrease in cytoplasmic iron levels.

Wu and colleagues showed reciprocal control of iron regulatory protein express H-ferritin and IRP2 by c-Myc and suggest a role for c-Myc in the regulation of cytoplasmic iron.  As both c-Myc and S1c11a1 modulate cytoplasmic iron, but in opposite directions, a role for c-Myc in the regulation of S1c11a1 was evaluated.  c-Myc co-transfection into both Cos1 and RAW264.7 macrophage lineage cells repressed expression of S1c11a1 promoter driven reporter constructs. An initiator (Inr) element flanking the transcriptional start site is a candidate site for the inhibition as c-Myc repression was observed on a 34bp region of 5’ flanking sequence containing only 2 Inr elements and a consensus Sp1 binding site.  Down regulation of the S1c11a1 promoter by c-Myc is though to involve the Inr binding protein Miz-1 (Myc interacting zinc finger protein-1).

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