Too MAD or not MAD enough: The duplicitous role of the spindle assembly checkpoint protein MAD2 in cancer

MAD2 is an intriguing protein, which has been associated with poor survival in cancer. Depending on the organ-specific cancer, either high expression or low expression levels have been correlated with low survival rates in patients. MAD2 is also a marker of contradiction. The normal function of MAD2 is to accumulate at kinetochores and generate a wait signal preventing the cell from progressing to anaphase of the cell cycle until the spindle microtubules have correctly aligned with the kinetochores on each chromosome. This process ensures that sister chromatids segregate correctly into each new daughter cell upon cellular division. Thus, the correct function of MAD2 and this crucial cell cycle checkpoint, the spindle assembly checkpoint (SAC), is essential for faithful replicative cell division, the prevention of chromosomal abnormalities and the development of cancer. Surprisingly when MAD2 is supressed for example through siRNA, this results in the induction of cellular senescence or cell cycle arrest. This is an inherent contradiction as normally the dispersement of MAD2 would signal to a cell that they should proceed to anaphase as spindle microtubules have correctly aligned with each chromatid for cell division. In the inverse setting; a second contradiction, high MAD2 expression in cancer patients generally correlates with abnormal chromosome number. However, in normal cells high expression of MAD2 would limit this by generating a wait signal to prevent the cell from proceeding through the cell cycle. In this review article we aim to make sense of the MADness and review the current knowledge of MAD2 and its role in cancer. •MAD2 is a spindle assembly checkpoint protein which prevents chromosomal abnormalities such as aneuploidy and tetraploidy.•MAD2 is overexpressed in cancers with chromosomal abnormalities and correlates with poor prognosis.•Low levels of MAD2 in organ specific cancers correlates with poor survival and a senescent phenotype.•MAD2 may help facilitate triage and selective targeting of senescent tumours or those containing chromosomal abnormalities•MAD2 is regulated by multiple mechanisms including hypoxia, and the action of microRNAs and protein regulators.