To grant faithful chromosome segregation, the spindle assembly checkpoint (SAC) delays mitosis exit until mitotic spindle assembly. An exceedingly prolonged mitosis, however, promotes cell death and by this means antimicrotubule cancer drugs (AMCDs), that impair spindle assembly, are believed to kill cancer cells. Despite malformed spindles, cancer cells can, however, slip through SAC, exit mitosis prematurely and resist killing. We show here that the Fcp1 phosphatase and Wee1, the cyclin B-dependent kinase (cdk) 1 inhibitory kinase, play a role for this slippage/resistance mechanism. During AMCD-induced prolonged mitosis, Fcp1-dependent Wee1 reactivation lowered cdk1 activity, weakening SAC-dependent mitotic arrest and leading to mitosis exit and survival. Conversely, genetic or chemical Wee1 inhibition strengthened the SAC, further extended mitosis, reduced antiapoptotic protein Mcl-1 to a minimum and potentiated killing in several, AMCD-treated cancer cell lines and primary human adult lymphoblastic leukemia cells. Thus, the Fcp1-Wee1-Cdk1 (FWC) axis affects SAC robustness and AMCDs sensitivity.

The Fcp1-Wee1-Cdk1 axis affects spindle assembly checkpoint robustness and sensitivity to antimicrotubule cancer drugs / Visconti, Roberta; DELLA MONICA, Rosa; Palazzo, Luca; D'Alessio, F.; Raia, M.; Improta, S.; Villa, MARIA ROSARIA; DEL VECCHIO, Luigi; Grieco, Domenico. - In: CELL DEATH AND DIFFERENTIATION. - ISSN 1350-9047. - 22:9(2015), pp. 1551-1560. [10.1038/cdd.2015.13]

The Fcp1-Wee1-Cdk1 axis affects spindle assembly checkpoint robustness and sensitivity to antimicrotubule cancer drugs

VISCONTI, ROBERTA;DELLA MONICA, ROSA;PALAZZO, LUCA;VILLA, MARIA ROSARIA;DEL VECCHIO, LUIGI;GRIECO, DOMENICO
2015

Abstract

To grant faithful chromosome segregation, the spindle assembly checkpoint (SAC) delays mitosis exit until mitotic spindle assembly. An exceedingly prolonged mitosis, however, promotes cell death and by this means antimicrotubule cancer drugs (AMCDs), that impair spindle assembly, are believed to kill cancer cells. Despite malformed spindles, cancer cells can, however, slip through SAC, exit mitosis prematurely and resist killing. We show here that the Fcp1 phosphatase and Wee1, the cyclin B-dependent kinase (cdk) 1 inhibitory kinase, play a role for this slippage/resistance mechanism. During AMCD-induced prolonged mitosis, Fcp1-dependent Wee1 reactivation lowered cdk1 activity, weakening SAC-dependent mitotic arrest and leading to mitosis exit and survival. Conversely, genetic or chemical Wee1 inhibition strengthened the SAC, further extended mitosis, reduced antiapoptotic protein Mcl-1 to a minimum and potentiated killing in several, AMCD-treated cancer cell lines and primary human adult lymphoblastic leukemia cells. Thus, the Fcp1-Wee1-Cdk1 (FWC) axis affects SAC robustness and AMCDs sensitivity.
2015
The Fcp1-Wee1-Cdk1 axis affects spindle assembly checkpoint robustness and sensitivity to antimicrotubule cancer drugs / Visconti, Roberta; DELLA MONICA, Rosa; Palazzo, Luca; D'Alessio, F.; Raia, M.; Improta, S.; Villa, MARIA ROSARIA; DEL VECCHIO, Luigi; Grieco, Domenico. - In: CELL DEATH AND DIFFERENTIATION. - ISSN 1350-9047. - 22:9(2015), pp. 1551-1560. [10.1038/cdd.2015.13]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/618743
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