Perera, Nirmal; (2017) The role of YAP 1 in regulating epithelial-mesenchymal transition. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

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.

Type:	Thesis (Doctoral)
Qualification:	Ph.D
Title:	The role of YAP 1 in regulating epithelial-mesenchymal transition
Event:	University College London
Language:	English
UCL classification:	UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI:	https://discovery.ucl.ac.uk/id/eprint/10024780

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