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Title: An investigation into the synergism between bovine papillomavirus type 4 and the flavonoid quercetin in the transformation of primary bovine palate fibroblasts
Author: Beniston, Richard G.
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1999
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Bovine papillomavirus type 4 (BPV 4) infects the upper alimentary canal of cattle causing benign papillomas which can progress to squamous carcinomas in cattle grazing on bracken fern (BF). A single treatment with quercetin, a well characterised and potent mutagen found in BF, can cause full oncogenic transformation of cells partially transformed by BPV-4. Quercetin elevates the activity of the BPV-4 enhancer/promoter element (LCR) by up to four fold but this cannot fully explain the observed effect as the timing of quercetin exposure is critical for full transformation of the cells. We show that quercetin exposure arrests normal PalF cells in the G1 phase of the cell cycle, and this G1 arrest correlates with an increase in p53 protein levels and transcriptional activity. Cells transformed by expression of either BPV 4 E7 and Ha-ras or the BPV4 genome and Ha-ras, fail to arrest in G1 after subsequent quercetin treatments. In these cells which are transformed but non-tumorigenic, p53 protein is elevated and transcriptionally activated in response to quercetin exposure. Yet the lack of cell cycle arrest is probably due to the viral protein E7 inhibiting p2Waf1/Cip1. In the transformed tumorigenic cells the failure to arrest in the G1 phase of the cell cycle is also evident. p53 protein is still present and even its stabilisation in response to quercetin can be observed in some cell lines, however p53 transcriptional activity is inhibited, probably as a result of p53 mutation. Additionally the protein which mediates p53 dependent cell cycle arrest, p2Waf1/Cip1 is also absent from all the tumorigenic cells lending further evidence to the loss of p53 as a transcriptional activator. Here we propose a model in which in normal cells quercetin induces G1 arrest, mediated by p53. Abrogation of this arrest by BPV-4 E7 allows the cell to proliferate allowing the accumulation of inheritable damage, including mutations of the p53 gene at later stages. The net effect of this is full tumorigenic transformation of the cell.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available