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Lookup NU author(s): Dr Kelly Jackson,
Dr Jill McKay,
Professor John Mathers,
Professor Dianne Ford
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Maintenance of cellular zinc homeostasis includes regulating the expression of cell membrane zinc transporters. Knowledge about the mechanisms underlying changes in mammalian zinc transporter mRNA abundance is poor. We demonstrated that when expressed in Chinese hamster ovary cells as N-terminal fusions to green fluorescent protein, two splice variants of ZnT5 adopt different subcellular locations (either in the Golgi apparatus or throughout the cell, including at the plasma membrane) indicating discrete roles in cellular zinc homeostasis. We demonstrated, using a β-galactosidase reporter gene, that both splice variants were expressed from a promoter region that was transcriptionally repressed by increased extracellular zinc (150 μM compared with 3 μM; ∼40%) and by extracellular zinc depletion, using the chelator N,N,N′,N′-tetrakis(2-pyridylmethyl) ethylenediamine (∼20%). We mapped the zinc-responsive element to the region -154 to +50, relative to the predicted start of transcription, and showed that a consensus metal response element sequence (-410 to -404) was not responsible for these effects. Changes in ZnT5 mRNA abundance in Caco-2 cells at different zinc concentrations were in parallel to the changes in promoter activity (∼40% reduction at 150 μM zinc) but in the presence of actinomycin D, to prevent transcription, we observed a marked stabilization (1.7-2-fold accumulation over 24 h) of ZnT5 mRNA. We conclude that effects of zinc on ZnT5 transcription and mRNA stability act in opposition to balance mRNA abundance for cellular zinc homeostasis. To our knowledge, this is the first report that zinc affects the stability of a transcript with a direct role in cellular zinc homeostasis. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.
Author(s): Jackson KA, Helston RM, McKay JA, O'Neill ED, Mathers JC, Ford D
Publication type: Article
Publication status: Published
Journal: Journal of Biological Chemistry
ISSN (print): 0021-9258
ISSN (electronic): 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology, Inc.
PubMed id: 17234632
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