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J. Biol. Chem., Vol. 282, Issue 14, 10423-10431, April 6, 2007

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Splice Variants of the Human Zinc Transporter ZnT5 (SLC30A5) Are Differentially Localized and Regulated by Zinc through Transcription and mRNA Stability^*

Kelly A. Jackson, Rachel M. Helston, Jill A. McKay, Elaine D. O'Neill, John C. Mathers, and Dianne Ford¹

From the Human Nutrition Research Centre, Institute for Cell and Molecular Biosciences, and School of Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4NN, United Kingdom

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 -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.

Received for publication, November 13, 2006 , and in revised form, January 17, 2007.

^* This work was supported in part by the United Kingdom Biotechnology and Biological Sciences Research Council Grant 13D/18271 (to D. F. and J. C. M.) and by a research studentship from the Medical Research Council (to K. A. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Inst. for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom. Tel.: 44-0-1912225986; Fax: 44-0-1912227424; E-mail: dianne.ford{at}ncl.ac.uk.

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