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Title: RASSF1A regulation of transcription factors in tumourigenesis and stem cell fate determination
Author: Papaspyropoulos, Angelos
ISNI:       0000 0004 5366 8848
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2014
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RASSF1A silencing is the most widely reported epigenetic event in sporadic human malignancies and is increasingly observed to be associated with poorer prognosis and outcome in lung, breast and bladder cancers amongst others. By performing a genetic screen in mice using Sleeping Beauty (SB) transposon-mediated insertional mutagenesis, we identified candidate genes associated with tumourigenesis in the absence of Rassf1a. A top hit in our screen was the terminal differentiation transcription factor Runx2. In this study, we describe how together loss of RASSF1A and RUNX2 exacerbate oncogenic YAP1-TEAD complexes and how RUNX2, p73 and TEAD effectively compete for YAP1 association. Interestingly, YAP1-TEAD complexes, as well as RUNX factors have been known to be important regulators of embryonic development by affecting cell fate. We show that RASSF1A is a novel regulator of stem cell pluripotency by introducing a cross link between the Hippo and Wnt signalling pathways, via TEAD and β-catenin. More specifically, we demonstrate that RASSF1A is a barrier to somatic cell reprogramming by activating differentiation circuits, but its loss results in upregulation of the core stem cell marker network (NANOG, OCT4 and SOX2) in embryonic stem cells and the pre-implantation mouse embryo. In addition, we find that deregulation of the Hippo pathway in the absence of RASSF1A also leads to increased prevalence of stem cell characteristics in cancer and higher proportion of 'cancer stem cells'. This effect is mediated through both YAP and its paralog TAZ. Finally, we show that a second isoform of RASSF1, RASSF1C, the expression of which is maintained in cancers, contributes to cancer stem cell generation through a similar mechanism. This work concentrates on establishing the biology of RASSF1A in normal tissue and answering whether the broad prognostic value in tumours from biologically distinct tissues is due to a fundamental control of stem cell pluripotency.
Supervisor: O'Neill, Eric Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medical Sciences