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UBC Theses and Dissertations

Distinct functions for the highly related PP2A B55 regulatory subunits (B alpha and B delta) in cell cycle regulation and tumourigenesis Sommerfeld, Dominik


Progression through the phases of the cell cycle (G1, S, G2, and mitosis) is largely driven by the coordinated activities of protein kinases and phosphatases, which orchestrate the phase-specific phosphorylation of proteins. Protein Phosphatase 2A (PP2A) – a heterotrimeric holoenzyme complex composed of a scaffold (A), catalytic (C), and variable regulatory (B) subunit – has emerged as an essential cell cycle regulator. Specifically, PP2A complexes containing the B55 family of regulatory subunits (PP2A-B55) have been implicated in the control of various cell cycle phases. My studies investigated isoform-specific roles of the two highly related and abundantly expressed B55 subunits, Bα and Bδ, in the regulation of G1, S, G2 phase and mitotic progression. Synchronization of HeLa cell populations at various stages of the cell cycle revealed that the Bα and Bδ subunits differentially regulate the kinetics of all cell cycle phases. Specifically, these highly related isoforms exert opposing effects on G1 phase progression, and Bα but not Bδ regulates progression through S phase. Furthermore, my studies demonstrate that the Bα and Bδ subunits play distinct roles in the control of mitotic exit progression, where Bδ regulates early and Bα mediates late mitotic exit events. PP2A-B55 complexes are believed to negatively regulate entry into mitosis by antagonizing CDK1 activation and CDK1-mediated mitotic substrate phosphorylation. While I found that PP2A-Bδ indeed antagonizes mitotic entry, my studies surprisingly revealed that PP2A-Bα promotes proper mitotic entry and progression. Specifically, loss of Bα resulted in the degradation of mitotic regulators, defective activation of CDK1 and other mitotic kinases, and the collapse of a pre-mitotic state during G2 phase. Deregulation of CDK1 activation is associated with mitotic defects, reduplication of the genome, and genome instability in cancer cells. Therefore, I investigated whether loss of Bα may precipitate genome instability. Depletion of Bα (but not Bδ) increased the incidence of cytokinesis failure and genome reduplication, and lead to polyploidization. PP2A activity is frequently attenuated in human tumours, with recent studies demonstrating loss of Bα subunit expression in various cancers. My findings suggest that Bα loss may support tumourigenesis by predisposing cells to polyploidization and genome instability.

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