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Title: The p53 family, septin scaffolds and epithelial ovarian cancer
Author: Hinds, Lynsey
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2013
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The septin GTP binding proteins are recognized as a novel part of the cytoskeleton and are known to form hetero-oligomeric complexes and higher order structures. The human SEPT9 gene has a complex genomic architecture with 18 transcripts generated through shuffling of six 5' ends and three 3' ends. Two transcripts with unique 5' ends (SEPT9_v4 and SEPT9_v4*) encode the same protein. Five different amino termini isoforms are recognized (SEPT9jl-i5) with j4 and j5 truncated versions of the larger isoforms. In neoplasia the relative • ratio of transcripts changes with upregulation of SEPT9_v4*, a transcript that is translated with enhanced efficiency leading to increased SEPT9j4. This study examined the effect of overexpression of the individual SEPT9 isoforms on endogenous SEPT9 and SEPT6 scaffolds and shows how SEPT9j4 and SEPT9j5 cause disruption of both endogenous SEPT6 and SEPT9 containing filaments. The thesis next examined how one of these small isoforms is regulated. Using a combination of sequence analysis and ChIP-seq, putative p53 and p63 binding sites upstream and downstream of the first exon of SEPT9_ v4* were examined. ChIP confirmed the binding of p53 and p63 to one of these regions, namely 468(D), upstream of SEPT9_v4*. Utilisation of a luciferase reporter gene construct also demonstrated that this specific site is regulated by both p53 and p63. Furthermore, quantitative profiling of SEPT9 transcript expression in a cohort of FFPE ovarian tumours before and after combined chemotherapy was performed. qRT-PCR analysis results revealed a significant elevation of SEPT9_vl, v2, v3, v4* and v5 post-chemotherapy but no statistically significant change in SEPT9_v4 expression. Knowing that overexpression of SEPT9_v4* in cells results in enhanced survival in the presence of Paclitaxel and that induction of SEPT9_v4* occurs following treatment With DNA damaging agents poses the question should we be treating ovarian tumours simultaneously with platinum and taxane agents?
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available