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Mechanisms of mammalian zinc-regulated gene expression

Lookup NU author(s): Dr Kelly Jackson, Dr Ruth Valentine, Lisa Coneyworth, Professor John Mathers, Professor Dianne Ford

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Abstract

Mechanisms through which gene expression is regulated by zinc are central to cellular zinc homoeostasis. In this context, evidence for the involvement of zinc dyshomoeostasis in the aetiology of diseases, including Type 2 diabetes, Alzheimer's disease and cancer, highlights the importance of zinc-regulated gene expression. Mechanisms elucidated in bacteria and yeast provide examples of different possible modes of zinc- sensitive gene regulation, involving the zinc-regulated binding of transcriptional activators and repressors to gene promoter regions. A mammalian transcriptional regulatory mechanism that mediates zinc-induced transcriptional up-regulation, involving the transcription factor MTF1 (metal-response element-binding transcription factor 1), has been studied extensively. Gene responses in the opposite direction (reduced mRNA levels in response to increased zinc availability) have been observed in mammalian cells, but a specific transcriptional regulatory process responsible for such a response has yet to be identified. Examples of single zinc-sensitive transcription factors regulating gene expression in opposite directions are emerging. Although zinc-induced transcriptional repression by MTF1 is a possible explanation in some specific instances, such a mechanism cannot account for repression by zinc of all mammalian genes that show this mode of regulation, indicating the existence of as yet uncharacterized mechanisms of zinc-regulated transcription in mammalian cells. in addition, recent findings reveal a role for effects of zinc on mRNA stability in the regulation of specific zinc transporters. Our studies on the regulation of the human gene SLC30A5 (solute carrier 30AS), which codes for the zinc transporter ZnT5, have revealed that this gene provides a model system by which to study both zinc-induced transcriptional down-regulation and zinc-regulated mRNA stabilization.


Publication metadata

Author(s): Jackson KA, Valentine RA, Coneyworth LJ, Mathers JC, Ford D

Publication type: Article

Publication status: Published

Journal: Biochemical Society Transactions

Year: 2008

Volume: 36

Issue: 6

Pages: 1262-1266

ISSN (print): 0300-5127

ISSN (electronic): 1470-8752

Publisher: Portland Press Ltd.

URL: http://dx.doi.org/10.1042/BST0361262

DOI: 10.1042/BST0361262


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