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Title: The role of YAP 1 in regulating epithelial-mesenchymal transition
Author: Perera, Nirmal
ISNI:       0000 0004 7227 2021
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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The Yes-associated protein 1 (YAP1) is an oncogenic transcriptional co-activator, which is negatively regulated by the Hippo signalling pathway. If the Hippo pathway is deregulated, YAP1 can translocate to the nucleus where it interacts with various transcription factors to drive transcription. Suppressing YAP1 as a therapeutic strategy has attracted considerable interest, especially since YAP1 and oncogenic RAS have been shown to interact in different tumour models. I evaluated the role(s) of YAP1 in transforming non-tumourigenic epithelial cells along the epithelial-mesenchymal transition (EMT) spectrum. Using a tetracycline-inducible expression system, I found that induced YAP1 overexpression in non-tumourigenic mouse Eph4 cells resulted in the upregulation of the mesenchymal markers, demonstrating a partial EMT. As a comparison, H-RAS overexpression in Eph4 cells resulted in E-CADHERIN relocalization away from the cell-cell junctions, also demonstrating a partial EMT. Co- expression of H-RAS and YAP1 resulted in a transition further along the EMT spectrum. However, YAP1 overexpression alone did not enhance cell migration or proliferation, whereas single overexpression of H-RAS did. Therefore, mutations which lead to overexpression of oncogenic RAS can be considered ‘driver’ mutations as they confer a significant tumourigenic potential to cancer cells. In contrast, although the upregulation of mesenchymal markers by YAP1 may also confer a survival advantage, YAP1 overexpression is not sufficient to trigger E-CADHERIN relocalization. Thus, mutations leading to YAP1 overexpression are neither ‘driver’ or ‘passenger’ mutations. Instead mutations leading to YAP1 overexpression are likely to represent an intermediate between a ‘driver’ and ‘passenger’ mutation. Hence I am referring to them as a ‘co-pilot’ of tumourigenesis.
Supervisor: Hergovich, Alexander Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available