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The nuclear function of dystroglycan in prostate cancer

Mathew, Grinu (2011) The nuclear function of dystroglycan in prostate cancer. PhD thesis, University of Sheffield.

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ABSTRACT In the UK, prostate cancer (CaP) is the second most common cause of cancer death in men. Loss of β-dystroglycan (DG) is associated with the progression of CaP. DG is a versatile signal transducing adhesion receptor that links cellular cytoskeleton to the basement membrane. Disruption of the link between cell adhesion proteins and the basement membrane in neoplastic tissue is an important precursor to cancer cell invasion leading to metastasis. However, the mechanisms that regulate the functionality of β-DG in CaP have not been thoroughly investigated. The data generated in this thesis work propose key mechanisms involving the regulation and novel nuclear function of β-DG in CaP cells. The study demonstrates an involvement of the androgen receptor (AR) in stimulating a loss of β-DG from the cell membrane. A novel finding is the androgen induced nuclear localisation of β-DG in CaP cells. Interestingly, the study also reveals a relevant mitogen induced cell cycle regulation of β-DG. The data manifests a potential link between translocation of β-DG to the nucleus and cell cycle progression. To investigate if post-translational modification of β-DG is involved in the fragmentation and loss of β-DG from the membrane, an antibody that recognises phosphorylated (pY892) DG (pDG) was used. On probing with the pDG antibody, β-DG was detected exclusively in the nucleus. Its localisation to the nucleus suggested a novel nuclear role of β-DG. Using the ELM functional site prediction tool, a monopartite nuclear localisation sequence was predicted on the juxtamembrane region of the cytoplasmic domain of β-DG (cβ-DG). cβ-DG was transiently over expressed in CaP cell lines. A robust translocation of cβ-DG to the nucleus was observed, whereas a construct with a mutated NLS (cβ-DG Δ NLS) was targeted to the cytoplasm. These results demonstrate the presence of a functional NLS on cβ-DG. To further study the functional role of β-DG in the nucleus of CaP cells, a microarray analysis comparing prostate cell lines transfected with the cβ-DG and cβ-DG Δ NLS constructs was performed. The identification of distinct set of genes related to CaP, with altered gene expression patterns, reveals a definite nuclear role of cβ-DG in CaP. The loss of β-DG from the membrane and its nuclear translocation in CaP may be a precursor to cancer invasion and metastasis. Hence, preventing the loss of β-DG from the membrane in CaP patients may prove to be an important therapeutic intervention.

Item Type: Thesis (PhD)
Keywords: dystroglycan, prostate cancer, nucleus
Academic Units: The University of Sheffield > Faculty of Science (Sheffield) > Biomedical Science (Sheffield)
The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Biomedical Science (Sheffield)
Depositing User: ms grinu mathew
Date Deposited: 20 Dec 2011 14:41
Last Modified: 08 Aug 2013 08:47
URI: http://etheses.whiterose.ac.uk/id/eprint/1976

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