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Aurora A, MCAK, and Kif18b promote Eg5-independent spindle formation

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 w...

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Autores principales: van Heesbeen, Roy G. H. P., Raaijmakers, Jonne A., Tanenbaum, Marvin E., Halim, Vincentius A., Lelieveld, Daphne, Lieftink, Cor, Heck, Albert J. R., Egan, David A., Medema, René H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509784/
https://www.ncbi.nlm.nih.gov/pubmed/27354041
http://dx.doi.org/10.1007/s00412-016-0607-4
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author van Heesbeen, Roy G. H. P.
Raaijmakers, Jonne A.
Tanenbaum, Marvin E.
Halim, Vincentius A.
Lelieveld, Daphne
Lieftink, Cor
Heck, Albert J. R.
Egan, David A.
Medema, René H.
author_facet van Heesbeen, Roy G. H. P.
Raaijmakers, Jonne A.
Tanenbaum, Marvin E.
Halim, Vincentius A.
Lelieveld, Daphne
Lieftink, Cor
Heck, Albert J. R.
Egan, David A.
Medema, René H.
author_sort van Heesbeen, Roy G. H. P.
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00412-016-0607-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-55097842017-07-28 Aurora A, MCAK, and Kif18b promote Eg5-independent spindle formation van Heesbeen, Roy G. H. P. Raaijmakers, Jonne A. Tanenbaum, Marvin E. Halim, Vincentius A. Lelieveld, Daphne Lieftink, Cor Heck, Albert J. R. Egan, David A. Medema, René H. Chromosoma Original Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00412-016-0607-4) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2016-06-29 2017 /pmc/articles/PMC5509784/ /pubmed/27354041 http://dx.doi.org/10.1007/s00412-016-0607-4 Text en © The Author(s) 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
van Heesbeen, Roy G. H. P.
Raaijmakers, Jonne A.
Tanenbaum, Marvin E.
Halim, Vincentius A.
Lelieveld, Daphne
Lieftink, Cor
Heck, Albert J. R.
Egan, David A.
Medema, René H.
Aurora A, MCAK, and Kif18b promote Eg5-independent spindle formation
title Aurora A, MCAK, and Kif18b promote Eg5-independent spindle formation
title_full Aurora A, MCAK, and Kif18b promote Eg5-independent spindle formation
title_fullStr Aurora A, MCAK, and Kif18b promote Eg5-independent spindle formation
title_full_unstemmed Aurora A, MCAK, and Kif18b promote Eg5-independent spindle formation
title_short Aurora A, MCAK, and Kif18b promote Eg5-independent spindle formation
title_sort aurora a, mcak, and kif18b promote eg5-independent spindle formation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509784/
https://www.ncbi.nlm.nih.gov/pubmed/27354041
http://dx.doi.org/10.1007/s00412-016-0607-4
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