Exploring the roles of the centrosomal RASSF proteins, RASSF1A & RASSF7, in stem cells & cancer

Thesis

The Ras – Association Domain Family (RASSF) is a group of ten structurally related proteins that have been linked to a series of human pathologies. RASSF1A is the most widely studied member of this group and is a bona fide tumour suppressor gene that has been reported as the most frequently epigenetically silenced gene in human sporadic malignancies. Loss of RASSF1A expression is linked to poor prognosis and a more aggressive clinical phenotype. Recently, RASSF1A has been linked to the regulation of pluripotency via modulation of the Hippo pathway and the transcriptional output of YAP associated genes. Here, we present evidence that the asymmetric localisation and subsequent inheritance of RASSF1A can influence the fate determination of differentiating stem cells. We propose that this event is the molecular basis of the clinical observation that RASSF1A loss leads to increased stem cell signatures in patient tumours. We also demonstrate that the asymmetry of RASSF1A is correlated to centrosome age and describe for the first time a role for RASSF1A in the assembly of the primary cilium, an important sensory organelle involved in signal transduction and development. Furthermore, we present an explorative study of RASSF7 function. RASSF7 is a widely-underexplored member of the RASSF group. It functions typically as an oncogene, yet relatively little is known about its molecular role. We show that RASSF7 interacts with the Hippo core kinase MST2 and has an important role in its subcellular localisation. This thesis focuses primarily on further establishing the molecular roles of RASSF1A and RASSF7 to determine how their deregulation leads to tumourigenesis.

Authors: Bradley, L

• DOI: 10.5287/ora-wrzw06rxe
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English