Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.713296
Title: Dystroglycan in the nucleus and the cell cycle
Author: Jacobs, Laura
ISNI:       0000 0004 6350 4425
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2017
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Abstract:
Dystroglycan is a ubiquitously expressed adhesion receptor and signalling scaffold found at the plasma membrane. DG function at the PM is disrupted in multiple human diseases including muscular dystrophy and epithelial carcinomas. More recently DG has also been identified in the nucleus of many cell types, however its nuclear functions and the mechanisms of its nuclear localisation are relatively poorly understood. In support of a growing number of reports, in this thesis ßDG was found to localise at the nuclear envelope, nucleoplasm and distinct nuclear foci in multiple prostate cell lines, normal and cancerous. Furthermore, in fibroblasts lacking DG, nuclear morphology was severely disrupted, supporting a role for DG in nuclear structure. The nuclear levels of ßDG are variable suggesting a dynamic regulation. DG protein levels and localisation have previously been reported to be regulated in a cell cycle dependent manner. Upon investigation via immunoblots, the nuclear levels of ßDG also appear to slightly fluctuate in a cell cycle dependent manner, with an increase in the nuclear levels of a phosphorylated form (pY892) of ßDG weakly correlating with cells in S phase following quantification, however this observation was not supported via immunofluorescence analysis and requires additional investigation. To further understand the precise mechanisms of nuclear translocation of ßDG we investigated a role for regulatory post-translational modification, specifically phosphorylation at residue T788 within the c-terminal of ßDG. Whilst mutations at residue T788 did not clearly affect the nuclear localisation of ßDG, preliminary evidence suggests that this residue may be important in protein stability. Finally, it was observed that ßDG antibodies colocalised to the centrosome in immunofluorescence studies however this localisation was demonstrated to be an antibody artefact. Studying the functions and regulation of ßDG at intracellular locations is important to better understand the numerous roles of this multifunctional protein in maintaining cellular homeostasis and may provide further insights into its contribution to disease progression.
Supervisor: Winder, Steve J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.713296  DOI: Not available
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