Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine

Abstract

Addition of reversine to dividing cells ejects Mad1 and the RZZ complex from unattached kinetochores and prevents resolution of incorrect chromosome–microtubule attachments (see also related papers by Hewitt et al. and Maciejowski et al. in this issue).

Mps1 promotes rapid centromere accumulation of Aurora B

“…The relatively small time window in which Mps1 operates likely explains why the effect of Mps1 on Aurora B centromere localization was not previously detected [10,15].…”

“…Whereas expression of wt-INCENP did not improve alignment under these conditions, we observed a striking improvement when Aurora B localization to centromeres was restored by CB-INCENP expression (Fig 4A,B; supplementary Fig S4B online). Only mild chromosome misalignments persisted, which might reflect the Aurora B-independent role of Mps1 in chromosome biorientation [11,[13][14][15]28].…”

“…The error correction function of Mps1 has been attributed to the phosphorylation of the CPC subunit Borealin that is required for Aurora B activation [10]. However, Aurora B-independent mechanisms have also been proposed [11,[13][14][15]. Therefore it is unclear exactly how Mps1 promotes error correction.…”

Preferential killing of p53-deficient cancer cells by reversine

“…Previous studies indicate that submicromolar concentrations of reversine strongly and selectively inhibit the mitotic kinase MPS1, while higher doses in the low micromolar range are efficient against a panel of additional kinases, Aurora kinase A and B (AURKA and AURKB). 35 Thus, it may be speculated that the preferential killing of p53-insufficient cells by high-dose reversine may involve the simultaneous inhibition of multiple kinases.…”

“…Thus, a large number of p53 mutants can neither respond to stress by transactivating cell cycle-arresting inhibition. 34 Driven by these observations, we decided to investigate whether another commercially available MPS1 inhibitor, reversine, 35 would also be able to selectively kill TP53 -/-cells over their TP53 +/+ counterparts. We found that the specific inhibition of MPS1 with siRNAs or low-dose reversine preferentially kills TP53 +/+ rather than TP53 -/-cells.…”