Probing the catalytic functions of Bub1 kinase using the small molecule inhibitors BAY-320 and BAY-524

Baron, Anna P. and von Schubert, Conrad and Cubizolles, Fabien and Siemeister, Gerhard and Hitchcock, Marion and Mengel, Anne and Schröder, Jens and Fernández-Montalván, Amaury and von Nussbaum, Franz and Mumberg, Dominik and Nigg, Erich A.. (2016) Probing the catalytic functions of Bub1 kinase using the small molecule inhibitors BAY-320 and BAY-524. eLife, 5. e12187.

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Official URL: http://edoc.unibas.ch/42070/

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The kinase Bub1 functions in the spindle assembly checkpoint (SAC) and in chromosome congression, but the role of its catalytic activity remains controversial. Here, we use two novel Bub1 inhibitors, BAY-320 and BAY-524, to demonstrate potent Bub1 kinase inhibition both in vitro and in intact cells. Then, we compared the cellular phenotypes of Bub1 kinase inhibition in HeLa and RPE1 cells with those of protein depletion, indicative of catalytic or scaffolding functions, respectively. Bub1 inhibition affected chromosome association of Shugoshin and the chromosomal passenger complex (CPC), without abolishing global Aurora B function. Consequently, inhibition of Bub1 kinase impaired chromosome arm resolution but exerted only minor effects on mitotic progression or SAC function. Importantly, BAY-320 and BAY-524 treatment sensitized cells to low doses of Paclitaxel, impairing both chromosome segregation and cell proliferation. These findings are relevant to our understanding of Bub1 kinase function and the prospects of targeting Bub1 for therapeutic applications.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Cell Biology (Nigg)
UniBasel Contributors:Nigg, Erich A. and Baron, Anna and Von Schubert, Conrad Eberhard and Cubizolles, Fabien
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:eLife Sciences Publications
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:22 Sep 2016 09:03
Deposited On:22 Sep 2016 09:03

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