Microtubules do not promote mitotic slippage when the spindle assembly checkpoint cannot be satisfied

Abstract

When the spindle assembly checkpoint (SAC) cannot be satisfied, cells exit mitosis via mitotic slippage. In microtubule (MT) poisons, slippage requires cyclin B proteolysis, and it appears to be accelerated in drug concentrations that allow some MT assembly. To determine if MTs accelerate slippage, we followed mitosis in human RPE-1 cells exposed to various spindle poisons. At 37°C, the duration of mitosis in nocodazole, colcemid, or vinblastine concentrations that inhibit MT assembly varied from 20 to 30 h, revealing that different MT poisons differentially depress the cyclin B destruction rate during slippage. The duration of mitosis in Eg5 inhibitors, which induce monopolar spindles without disrupting MT dynamics, was the same as in cells lacking MTs. Thus, in the presence of numerous unattached kinetochores, MTs do not accelerate slippage. Finally, compared with cells lacking MTs, exit from mitosis is accelerated over a range of spindle poison concentrations that allow MT assembly because the SAC becomes satisfied on abnormal spindles and not because slippage is accelerated.

Length of mitotic arrest induced by microtubule-stabilizing drugs determines cell death after mitotic exit

“…Our experiments and those involving checkpoint adaptation involve processes, which are different from checkpoint recovery in which the checkpoint is inactivated due to repair of the initial damage. The mitotic arrest induced by spindle disruptive agents also can be released by the gradual loss of the checkpoint effector, cyclin B, despite the continued presence of spindle damage and the activation of upstream checkpoint proteins (29,30).…”

Low-dose laulimalide represents a novel molecular probe for investigating microtubule organization

“…mitotic slippage. [10][11][12][13][14][15] An agent that induces MT stabilization by engaging a unique site may provide new ways to study mitotic properties. Before laulimalide and the site that it occupies can be exploited for therapeutics or molecular probes, a more extensive investigation of cellular phenotype and mode of action is required.…”

USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora-A kinase

“…11 Besides alteration in the expression of tubulin or microtubuleassociated proteins and multidrug resistance, dysregulation of cellular pathways such as cell cycle control, cell proliferation, apoptosis and nuclear-cytoplasmic transport have been linked to taxane activity and resistance. 12 Numerous studies provide evidence that SAC has a role in taxane response, either enhancing sensitivity to these spindle toxins 13,14 or increasing mitotic arrest or 'resistance'. 15,16 Aurora-A kinase has been linked to taxane resistance; 17 it is amplified in breast cancer, 18 overexpressed in several tumors with poor prognosis and it is an emerging therapeutic target.…”