Examining the role of ZIP7 in zinc signalling mechanisms and its relevance to cancer

Almadani, Sara 2022. Examining the role of ZIP7 in zinc signalling mechanisms and its relevance to cancer. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Zinc is an essential trace element in the human body. The cellular zinc level is tightly regulated by zinc transporters, including the ZIP family, which has a role in increasing cytosolic zinc levels. The aberrant function of many ZIP channels has been associated with human diseases, including cancer. Our main focus is zinc transporter ZIP7 which is uniquely placed on the endoplasmic reticulum membrane. Despite this cellular localisation, ZIP7 appears to stain the nuclear membrane raising the issue that it can transport zinc into the nucleus as well as the cytosol. The present study evaluated the significance of ZIP7 gene expression in breast cancer using comprehensive bioinformatic analysis. Findings within this project support the hypothesis that ZIP7 might be considered a predictive biomarker for breast cancer prognosis and a novel therapeutic target for breast cancer. Imaging ZIP7 in MCF7 cells has suggested that ZIP7 and the active form of ZIP7 (pS275/S276 ZIP7) are located in the nuclear membrane. These data highlighted that ZIP7 could transport zinc from the endoplasmic reticulum store into the nucleus. This nuclear localisation of ZIP7 may play an essential role in cell growth but also position it to increase cancer development through access to transcription factors which have a zinc finger domain. It is crucial to understand the function of ZIP7 in the nuclear envelope so having discovered three potential nuclear localisation motifs in ZIP7, these were mutated by site-directed mutagenesis for experimental confirmation. The different functions of nuclear-located ZIP7 mutants were assessed by phospho-kinase arrays to examine the effect on the activation of downstream pathways. This study revealed that NLS3 (288AAAGGSTVPKDGPVRPQNAEEEAA311) is required for ZIP7 maximal activation. ZIP7 has already been implicated in cancer growth and proving the role of ZIP7 in nuclear zinc transport could have significant implications for future cancer therapy.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Pharmacy
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	25 May 2022
Last Modified:	14 Dec 2022 02:27
URI:	https://orca.cardiff.ac.uk/id/eprint/150014

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