Baron, Anna. On the regulation of chromosome segregation in human cells : implications of Bub1 Kinase inhibition during cell division. 2015, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_11590
Here we present a thorough characterization of two novel small-molecule ATP-competitive inhibitors of Bub1 kinase, BAY-320 and BAY-524, to demonstrate potent Bub1 kinase inhibition both in vitro and in intact cells. We compared the cellular phenotypes of Bub1 kinase inhibition in HeLa and RPE-1 cells with those of protein depletion, indicative of catalytic or scaffolding functions, respectively. We demonstrate that Bub1 inhibition resulted in the persistence of chromosome arm cohesion. Furthermore, Bub1 inhibition affected chromosome association of Shugoshin and the chromosomal passenger complex, without abolishing global Aurora B function. Bub1 cooperates with Haspin on CPC localization, as inhibition of both kinases showed an additive effect. But for all that, Bub1 kinase inhibition exerted only minor effects on mitotic progression, chromosome alignment or spindle checkpoint function. In striking contrast, Bub1 depletion impaired all the mentioned mitotic processes, arguing that Bub1 largely operates as a scaffolding protein.
Although, Bub1 inhibition seems to have little influence in mitotic fidelity, BAY-320 and BAY-524 treatment sensitized cells to low doses of Paclitaxel, resulting in remarkable impairment of 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.
|Advisors:||Nigg, Erich A. and Handschin, Christoph|
|Faculties and Departments:||05 Faculty of Science > Departement Biozentrum > Growth & Development > Cell Biology (Nigg)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||1 Online-Ressource (189 Seiten)|
|Last Modified:||27 Sep 2016 13:05|
|Deposited On:||27 Sep 2016 12:55|
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