A novel role for C-terminal binding proteins in the regulation of mitotic fidelity in breast cancer cells

C-terminal binding proteins (CtBPs) (CtBP1 and CtBP2) are dual-function proteins that act in the nucleus as transcriptional co-repressors and in the cytoplasm as regulators of mitotic Golgi fissioning. They have been implicated in the process of cellular transformation through their physical and functional interactions with the viral oncoproteins adenovirus E1A, and EBNA3C. Studies in which the expression or function of CtBPs has been suppressed in mammalian cells have independently identified both a role in suppressing apoptosis, through their regulation of transcription of proapoptotic genes, and a requirement for cell-cycle progression, dependent on their role in the Golgi. Here we have undertaken a holistic analysis of the phenotypic consequences of ablating CtBP expression in breast cancer-derived cell lines. We find that loss of CtBPs suppresses the proliferation of these lines through a combination of induction of apoptosis, reduction in cell-cycle progression into mitosis, and aberrations in transit through mitosis itself. This third phenotype includes errors in mitotic chromosome segregation, activation of, but failure to sustain, the spindle assembly checkpoint, diminished localisation of spindle checkpoint proteins at kinetochores, and a high rate of failure to complete cytokinesis. These represent novel roles for CtBPs in the regulation of critical stages of the cell division cycle.