Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Biochemistry

Supervisor

Dr. Caroline Schild-Poulter

Abstract

Ran-binding protein M (RanBPM) is an evolutionarily conserved nucleocytosolic protein that has been proposed to regulate various cellular processes, including protein stability, gene expression, receptor-mediated signalling pathways, cell adhesion, development, and apoptosis. Despite the multitude of functions attributed to RanBPM however, little is known regarding the precise mechanisms by which RanBPM executes these cellular roles. In this work, we seek to address this matter by describing functions for RanBPM in the regulation of apoptotic and pro-survival signalling pathways, and in cellular transformation.

We first identify RanBPM as a pro-apoptotic protein that regulates the activation of the intrinsic apoptotic signalling pathway in response to DNA damage. We show that RanBPM executes its pro-apoptotic functions by modulating the expression and localization of Bcl-2 family proteins. Next, we demonstrate that RanBPM functions as a novel inhibitor of the ERK1/2 signalling cascade, and that RanBPM regulates the expression of Bcl-2 factors through repression of this pathway. We also extend these analyses to show that RanBPM forms a complex with c-Raf, and that it prevents aberrant ERK1/2 signalling by destabilizing the c-Raf-Hsp90 complex, thus maintaining low cellular c-Raf expression. Our studies also implicate an important function for RanBPM in the regulation of gene expression programs. We find that disruption of RanBPM expression affects transcriptional networks involved in the regulation of organism development and tumourigenesis, and that decreased RanBPM levels alter the expression of factors involved in signal transduction through the Notch, Wnt, PI3K, and ERK1/2 pathways. Importantly, our work also reveals that the down-regulation of RanBPM expression is associated with the acquisition of markers of cellular transformation, specifically evasion from apoptosis, sustained proliferative signalling, and increased cellular migration and invasion, suggesting a novel tumour suppressor function for RanBPM. Taken together, our studies provide insight into the molecular mechanisms by which may RanBPM mediate its diverse biological functions, and reveal that altered RanBPM expression may have important ramifications in the regulation of organism development and disease pathogenesis.

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