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Title: An investigation into the function and regulation Of ERG Exon 7b
Author: Jumbe, Samantha
Awarding Body: University of the West of England
Current Institution: University of the West of England, Bristol
Date of Award: 2018
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The ETS family transcription factor ERG is a key oncoprotein in bone, blood, vascular and most notably prostate cancer where it is activated in at least 50% of cases. Of the several splice isoforms of ERG with variable biological activity those that include the cassette exon 7b are associated with aggressiveness and progression of disease in prostate cancer. Inclusion of exon 7b adds 24 amino-acids in frame to the central 'alternative domain' which also contains binding sites for other transcriptional regulators. Alignment of the amino acids of exon 7b showed it is evolutionary conserved in echinoderms emphasizing its functional importance. Splice switching oligonucleotides (SSO) targeting the splice sites for exon 7b were designed to induce exon 7b skipping. Successful SSO-induced skipping of exon 7b in the osteosarcoma MG63 cell line resulted in decreased cell migration, invasion and proliferation and increased apoptosis in vitro and reduced tumour growth in vivo. ERG was shown to bind to the promoter of tissue non-specific alkaline phosphatase, a marker of cell differentiation, and SSO-induced skipping of exon 7b attenuated its expression. Moreover several splicing regulatory elements and proteins were identified using bioinformatics prediction methods and an RNA pull down of the 3´ splice site of exon 7b identified several potential splicing regulatory proteins for this exon. This study provides evidence that exon 7b enhances the oncogenic activity of ERG. It also confirms that SSOs can be used to modify the splicing of key oncogenes, significantly affecting their function. SSOs that target oncogenes could potentially be developed as therapeutic agents. It also highlights the requirement to understand splicing regulation of disease associated splicing events in ETS transcription factors and has provided pilot data for further study of ERG exon 7b splicing regulation.
Supervisor: Not available Sponsor: Malawi Scholarship Fund
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: ERG transcription factor ; cancer ; alternative splicing ; splice switching oligonucleotides