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Molecular Cancer
Published in: Molecular Cancer 1/2011

Open Access 01-12-2011 | Research

Aurora-A inactivation causes mitotic spindle pole fragmentation by unbalancing microtubule-generated forces

Authors: Italia A Asteriti, Maria Giubettini, Patrizia Lavia, Giulia Guarguaglini

Published in: Molecular Cancer | Issue 1/2011

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Abstract

Background

Aurora-A is an oncogenic kinase playing well-documented roles in mitotic spindle organisation. We previously found that Aurora-A inactivation yields the formation of spindles with fragmented poles that can drive chromosome mis-segregation. Here we have addressed the mechanism through which Aurora-A activity regulates the structure and cohesion of spindle poles.

Results

We inactivated Aurora-A in human U2OS osteosarcoma cells either by RNA-interference-mediated silencing or treating cultures with the specific inhibitor MLN8237. We show that mitotic spindle pole fragmentation induced by Aurora-A inactivation is associated with microtubule hyperstabilisation. Silencing of the microtubule-stabilising factor ch-TOG prevents spindle pole fragmentation caused by inactivation of Aurora-A alone and concomitantly reduces the hyperstabilisation of microtubules. Furthermore, decreasing pole-directed spindle forces by inhibition of the Eg5 kinesin, or by destabilisation of microtubule-kinetochore attachments, also prevents pole fragmentation in Aurora-A-inactivated mitoses.

Conclusions

Our findings indicate that microtubule-generated forces are imbalanced in Aurora-A-defective cells and exert abnormal pressure at the level of spindle poles, ultimately causing their fragmentation. This study therefore highlights a novel role of the Aurora-A kinase in regulating the balance between microtubule forces during bipolar spindle assembly.
Appendix
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Literature
1.
Tanenbaum ME, Medema RH: Mechanisms of centrosome separation and bipolar spindle assembly. Dev Cell. 2010, 19: 797-806. 10.1016/j.devcel.2010.11.011CrossRefPubMed
2.
Walczak CE, Cai S, Khodjakov A: Mechanisms of chromosome behaviour during mitosis. Nat Rev Mol Cell Biol. 2010, 11: 91-102. 10.1038/nrg2737PubMedCentralPubMed
3.
4.
Gatlin JC, Bloom K: Microtubule motors in eukaryotic spindle assembly and maintenance. Semin Cell Dev Biol. 2010, 21: 248-254. 10.1016/j.semcdb.2010.01.015PubMedCentralCrossRefPubMed
5.
Kapoor TM, Mayer TU, Coughlin ML, Mitchison TJ: Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin Eg5. J Cell Biol. 2000, 150: 975-988. 10.1083/jcb.150.5.975PubMedCentralCrossRefPubMed
6.
Tanenbaum ME, Macurek L, Galjart N, Medema RH: Dynein, Lis1 and CLIP-170 counteract Eg5-dependent centrosome separation during bipolar spindle assembly. EMBO J. 2008, 27: 3235-3245. 10.1038/emboj.2008.242PubMedCentralCrossRefPubMed
7.
Barr AR, Gergely F: Aurora-A: the maker and breaker of spindle poles. J Cell Sci. 2007, 120: 2987-2996. 10.1242/jcs.013136CrossRefPubMed
8.
Vader G, Lens SM: The Aurora kinase family in cell division and cancer. Biochim Biophys Acta. 2008, 1786: 60-72.PubMed
9.
Sen S, Zhou H, White RA: A putative serine/threonine kinase encoding gene BTAK on chromosome 20q13 is amplified and overexpressed in human breast cancer cell lines. Oncogene. 1997, 14: 2195-2200. 10.1038/sj.onc.1201065CrossRefPubMed
10.
Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, Schryver B, Flanagan P, Clairvoyant F, Ginther C, Chan CSM, Novotny M, Slamon DJ, Plowman GD: A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 1998, 17: 3052-3065. 10.1093/emboj/17.11.3052PubMedCentralCrossRefPubMed
11.
Wang Y, Ji P, Liu J, Broaddus RR, Xue F, Zhang W: Centrosome-associated regulators of the G2/M checkpoint as targets for cancer therapy. Mol Cancer. 2009, 8: 8- 10.1186/1476-4598-8-8PubMedCentralCrossRefPubMed
12.
Lens SM, Voest EE, Medema RH: Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat Rev Cancer. 2010, 10: 825-841. 10.1038/nrc2964CrossRefPubMed
13.
Kitajima S, Kudo Y, Ogawa I, Tatsuka M, Kawai H, Pagano M, Takata T: Constitutive phosphorylation of aurora-a on ser51 induces its stabilization and consequent overexpression in cancer. PLoS One. 2007, 2: e944- 10.1371/journal.pone.0000944PubMedCentralCrossRefPubMed
14.
Man C, Rosa J, Yip YL, Cheung AL, Kwong YL, Doxsey SJ, Tsao SW: Id1 overexpression induces tetraploidization and multiple abnormal mitotic phenotypes by modulating aurora A. Mol Biol Cell. 2008, 19: 2389-2401. 10.1091/mbc.E07-09-0875PubMedCentralCrossRefPubMed
15.
Giubettini M, Asteriti IA, Scrofani J, De Luca M, Lindon C, Lavia P, Guarguaglini G: Control of Aurora-A stability through interaction with TPX2. J Cell Sci. 2011, 124: 113-122. 10.1242/jcs.075457PubMedCentralCrossRefPubMed
16.
Asteriti IA, Rensen WM, Lindon C, Lavia P, Guarguaglini G: The Aurora-A/TPX2 complex: a novel oncogenic holoenzyme?. Biochim Biophys Acta. 2010, 1806: 230-239.PubMed
17.
Lentini L, Amato A, Schillaci T, Di Leonardo A: Simultaneous Aurora-A/STK15 overexpression and centrosome amplification induce chromosomal instability in tumour cells with a MIN phenotype. BMC Cancer. 2007, 7: 212- 10.1186/1471-2407-7-212PubMedCentralCrossRefPubMed
18.
Lukasiewicz KB, Lingle WL: Aurora A, centrosome structure, and the centrosome cycle. Environ Mol Mutagen. 2009, 50: 602-619. 10.1002/em.20533CrossRefPubMed
19.
Meraldi P, Honda R, Nigg EA: Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53-/- cells. EMBO J. 2002, 21: 483-492. 10.1093/emboj/21.4.483PubMedCentralCrossRefPubMed
20.
Anand S, Penrhyn-Lowe S, Venkitaraman AR: AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell. 2003, 3: 51-62. 10.1016/S1535-6108(02)00235-0CrossRefPubMed
21.
Pérez de Castro I, de Cárcer G, Montoya G, Malumbres M: Emerging cancer therapeutic opportunities by inhibiting mitotic kinases. Curr Opin Pharmacol. 2008, 8: 375-383. 10.1016/j.coph.2008.06.013CrossRefPubMed
22.
De Luca M, Lavia P, Guarguaglini G: A functional interplay between Aurora-A, Plk1 and TPX2 at spindle poles. Cell Cycle. 2006, 5: 296-303. 10.4161/cc.5.3.2392CrossRefPubMed
23.
De Luca M, Brunetto L, Asteriti IA, Giubettini M, Lavia P, Guarguaglini G: Aurora-A and ch-TOG act in a common pathway in control of spindle pole integrity. Oncogene. 2008, 27: 6539-6549. 10.1038/onc.2008.252CrossRefPubMed
24.
Marumoto T, Honda S, Hara T, Nitta M, Hirota T, Kohmura E, Saya H: Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem. 2003, 278: 51786-51795. 10.1074/jbc.M306275200CrossRefPubMed
25.
Hoar K, Chakravarty A, Rabino C, Wysong D, Bowman D, Roy N, Ecsedy JA: MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy. Mol Cell Biol. 2007, 27: 4513-4525. 10.1128/MCB.02364-06PubMedCentralCrossRefPubMed
26.
Hunter AW, Caplow M, Coy DL, Hancock WO, Diez S, Wordeman L, Howard J: The kinesin-related protein MCAK is a microtubule depolymerase that forms an ATP-hydrolyzing complex at microtubule ends. Mol Cell. 2003, 11: 445-457. 10.1016/S1097-2765(03)00049-2CrossRefPubMed
27.
Gard DL, Becker BE, Josh Romney S: MAPping the eukaryotic tree of life: structure, function, and evolution of the MAP215/Dis1 family of microtubule-associated proteins. Int Rev Cytol. 2004, 239: 179-272.CrossRefPubMed
28.
Barr AR, Gergely F: MCAK-independent functions of ch-Tog/XMAP215 in microtubule plus-end dynamics. Mol Cell Biol. 2008, 28: 7199-7211. 10.1128/MCB.01040-08PubMedCentralCrossRefPubMed
29.
Cassimeris L, Becker B, Carney B: TOGp regulates microtubule assembly and density during mitosis and contributes to chromosome directional instability. Cell Motil Cytoskeleton. 2009, 66: 535-545. 10.1002/cm.20359CrossRefPubMed
30.
Cassimeris L, Morabito J: TOGp, the human homolog of XMAP215/Dis1, is required for centrosome integrity, spindle pole organization, and bipolar spindle assembly. Mol Biol Cell. 2004, 15: 1580-1590. 10.1091/mbc.E03-07-0544PubMedCentralCrossRefPubMed
31.
Meraldi P, Draviam VM, Sorger PK: Timing and checkpoints in the regulation of mitotic progression. Dev Cell. 2004, 7: 45-60. 10.1016/j.devcel.2004.06.006CrossRefPubMed
32.
Kufer TA, Silljé HHW, Roman K, Gruss OJ, Meraldi P, Nigg EA: Human TPX2 is required for targeting Aurora-A kinase to the spindle. J Cell Biol. 2002, 158: 617-623. 10.1083/jcb.200204155PubMedCentralCrossRefPubMed
33.
Sloane DA, Trikic MZ, Chu ML, Lamers MB, Mason CS, Mueller I, Savory WJ, Williams DH, Eyers PA: Drug-resistant aurora A mutants for cellular target validation of the small molecule kinase inhibitors MLN8054 and MLN8237. ACS Chem Biol. 2010, 5: 563-576. 10.1021/cb100053qCrossRefPubMed
34.
Toso A, Winter JR, Garrod AJ, Amaro AC, Meraldi P, McAinsh AD: Kinetochore-generated pushing forces separate centrosomes during bipolar spindle assembly. J Cell Biol. 2009, 184: 365-372. 10.1083/jcb.200809055PubMedCentralCrossRefPubMed
35.
Manning AL, Compton DA: Mechanisms of spindle-pole organization are influenced by kinetochore activity in mammalian cells. Curr Biol. 2007, 17: 260-265. 10.1016/j.cub.2006.11.071CrossRefPubMed
36.
DeLuca JG, Moree B, Hickey JM, Kilmartin JV, Salmon ED: hNuf2 inhibition blocks stable kinetochore-microtubule attachment and induces mitotic cell death in HeLa cells. J Cell Biol. 2002, 159: 549-555. 10.1083/jcb.200208159PubMedCentralCrossRefPubMed
37.
Fielding AB, Dobreva I, McDonald PC, Foster LJ, Dedhar S: Integrin-linked kinase localizes to the centrosome and regulates mitotic spindle organization. J Cell Biol. 2008, 180: 681-689. 10.1083/jcb.200710074PubMedCentralCrossRefPubMed
38.
Koffa MD, Casanova CM, Santarella R, Köcher T, Wilm M, Mattaj IW: HURP is part of a Ran-dependent complex involved in spindle formation. Curr Biol. 2006, 16: 743-754. 10.1016/j.cub.2006.03.056CrossRefPubMed
39.
Giet R, Uzbekov R, Cubizolles F, Le Guellec K, Prigent C: The Xenopus laevis aurora-related protein kinase pEg2 associates with and phosphorylates the kinesin-related protein XlEg5. J Biol Chem. 1999, 274: 15005-15013. 10.1074/jbc.274.21.15005CrossRefPubMed
40.
Sardon T, Pache RA, Stein A, Molina H, Vernos I, Aloy P: Uncovering new substrates for Aurora A kinase. EMBO Rep. 2010, 11: 977-984. 10.1038/embor.2010.171PubMedCentralCrossRefPubMed
41.
Kops GJ, Foltz DR, Cleveland DW: Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint. Proc Natl Acad Sci USA. 2004, 101: 8699-8704. 10.1073/pnas.0401142101PubMedCentralCrossRefPubMed
42.
Janssen A, Medema RH: Mitosis as an anti-cancer target. Oncogene. 2011, 30: 2799-2809. 10.1038/onc.2011.30CrossRefPubMed
43.
Huszar D, Theoclitou ME, Skolnik J, Herbst R: Kinesin motor proteins as targets for cancer therapy. Cancer Metastasis Rev. 2009, 28: 197-208. 10.1007/s10555-009-9185-8CrossRefPubMed
44.
Screpanti E, Santaguida S, Nguyen T, Silvestri R, Gussio R, Musacchio A, Hamel E, De Wulf P: A screen for kinetochore-microtubule interaction inhibitors identifies novel antitubulin compounds. PLoS One. 2010, 5: e11603- 10.1371/journal.pone.0011603PubMedCentralCrossRefPubMed
Metadata
Title
Aurora-A inactivation causes mitotic spindle pole fragmentation by unbalancing microtubule-generated forces
Authors
Italia A Asteriti
Maria Giubettini
Patrizia Lavia
Giulia Guarguaglini
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2011
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-10-131

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