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Ablation of the spindle assembly checkpoint by a compound targeting Mps1
Author(s) -
Schmidt Marc,
Budirahardja Yemima,
Klompmaker Rob,
Medema René H
Publication year - 2005
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/sj.embor.7400483
Subject(s) - microbiology and biotechnology , spindle checkpoint , chemistry , biology , spindle apparatus , biochemistry , cell division , cell
The spindle assembly checkpoint ensures accurate chromosome segregation by delaying anaphase initiation until all chromosomes are properly attached to the mitotic spindle. Here, we show that the previously reported c‐Jun amino‐terminal kinase (JNK) inhibitor SP600125 effectively disrupts spindle checkpoint function in a JNK‐independent fashion. SP600125 potently inhibits activity of the mitotic checkpoint kinase monopolar spindle 1 (Mps1) in vitro and triggers efficient progression through a mitotic arrest imposed by spindle poisons. Importantly, expression of an Mps1 mutant protein refractory to SP600125‐mediated inhibition restores spindle checkpoint function in the presence of SP600125, showing that its mitotic phenotype is induced by Mps1 inhibition in vivo . Remarkably, primary human cells are largely resistant to the checkpoint‐inactivating action of SP600125, suggesting the existence of Mps1‐independent checkpoint pathways that are compromised in tumour cells.