The Spindle Checkpoint: From Normal Cell Division to Tumorigenesis

Faithful chromosome segregation during each cell division is regulated by the spindle checkpoint. This surveillance mechanism monitors kinetochore-microtubule attachment and the integrity of the mitotic apparatus, delaying mitotic exit until all chromosomes are properly aligned at the metaphase plate. Failure of this mechanism can generate gross aneuploidy. Since its discovery, mutations in genes involved in the spindle checkpoint response were predicted to be serious candidates for the chromosomal instability phenotype observed in many tumors. During the last few years, significant advances have been made in understanding the molecular basis of the spindle checkpoint. However, many studies of tumor cell lines and primary cancer isolates have failed to show a direct correlation with mutations in spindle checkpoint components. Nevertheless, it was shown that many tumor cells have an abnormal spindle checkpoint. Therefore, better understanding of the molecular mechanisms involved in regulation of spindle checkpoint response are expected to provide important clues regarding the mechanisms underlying the emergence of neoplasia.