Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.589687
Title: Novel binding partners of PBF in thyroid tumourigenesis
Author: Sharma, Neil
ISNI:       0000 0004 5346 4730
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2014
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Abstract:
Thyroid cancer is the most common endocrine cancer, with a rising incidence. The proto-oncogene PBF is over-expressed in thyroid tumours, and the degree of over-expression is directly linked to patient survival. PBF causes transformation in vitro and tumourigenesis in vivo, with PBF-transgenic mice developing large, macro-follicular goitres, effects partly mediated by the internalisation and repression of the membrane-bound transporters NIS and MCT8. NIS repression leads to a reduction in iodide uptake, which may negatively affect the efficacy of radioiodine treatment, and therefore prognosis. Work within this thesis describes the use of tandem mass spectrometry to produce a list of potential binding partners of PBF. This will aid further research into the pathophysiology of PBF, not just in relation to thyroid cancer but also other malignancies. From this list, the interaction with three proteins was further investigated and validated by GST pull-down assays and/or co-immunoprecipitation. Thyroglobulin is an essential component of thyroid hormone synthesis. Preliminary studies suggested co-localisation with PBF within intra-cellular vesicles, although further research is needed to explore this functionally. Cortactin has a role in the cellular transport of proteins, and also promotes invadopodia formation and metastases in cancer. Co-localisation was observed in vesicles and at the membrane, with PBF additionally demonstrated in cell membrane projections – indicating a potential mechanism for the shuttling of PBF to and from the cell membrane, and its secretion. SRC is a tyrosine kinase intimately linked to cancer. SRC phosphorylated PBF, an effect abrogated by treatment with specific inhibitors, including PP1. Importantly, PP1 treatment was then found to increase iodide uptake in human primary thyroid cultures over-expressing PBF. Overall, these data describe a list of possible binding partners for PBF, and specifically identify a novel potential therapeutic strategy for iodide-refractory thyroid cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.589687  DOI: Not available
Keywords: R Medicine (General) ; RC0254 Neoplasms. Tumors. Oncology (including Cancer)
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