| Autor: |
van Heesbeen RGHP; Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Raaijmakers JA; Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Tanenbaum ME; Hubrecht Institute, The Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, the Netherlands., Halim VA; Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands., Lelieveld D; Cell Screening Core, Department of Cell Biology, Center for Molecular Medicine, University Medical Centre, Utrecht, The Netherlands., Lieftink C; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Heck AJR; Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands., Egan DA; Cell Screening Core, Department of Cell Biology, Center for Molecular Medicine, University Medical Centre, Utrecht, The Netherlands., Medema RH; Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. r.medema@nki.nl. |
| Abstrakt: |
Inhibition of the microtubule (MT) motor protein Eg5 results in a mitotic arrest due to the formation of monopolar spindles, making Eg5 an attractive target for anti-cancer therapies. However, Eg5-independent pathways for bipolar spindle formation exist, which might promote resistance to treatment with Eg5 inhibitors. To identify essential components for Eg5-independent bipolar spindle formation, we performed a genome-wide siRNA screen in Eg5-independent cells (EICs). We find that the kinase Aurora A and two kinesins, MCAK and Kif18b, are essential for bipolar spindle assembly in EICs and in cells with reduced Eg5 activity. Aurora A promotes bipolar spindle assembly by phosphorylating Kif15, hereby promoting Kif15 localization to the spindle. In turn, MCAK and Kif18b promote bipolar spindle assembly by destabilizing the astral MTs. One attractive way to interpret our data is that, in the absence of MCAK and Kif18b, excessive astral MTs generate inward pushing forces on centrosomes at the cortex that inhibit centrosome separation. Together, these data suggest a novel function for astral MTs in force generation on spindle poles and how proteins involved in regulating microtubule length can contribute to bipolar spindle assembly. |
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