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Aurora-A and ch-TOG act in a common pathway in control of spindle pole integrity

Oncogene volume 27, pages 6539–6549 (2008)Cite this article

Abstract

Mitotic spindle assembly is a highly regulated process, crucial to ensure the correct segregation of duplicated chromosomes in daughter cells and to avoid aneuploidy, a common feature of tumors. Among the most important spindle regulators is Aurora-A, a mitotic centrosomal kinase frequently overexpressed in tumors. Here, we investigated the role of Aurora-A in spindle pole organization in human cells. We show that RNA interference-mediated Aurora-A inactivation causes pericentriolar material fragmentation in prometaphase, yielding the formation of spindles with supernumerary poles. This fragmentation does not necessarily involve centrioles and requires microtubules (MTs). Aurora-A-depleted prometaphases mislocalize the MT-stabilizing protein colonic hepatic tumor-overexpressed gene (ch-TOG), which abnormally accumulates at spindle poles, as well as the mitotic centromere-associated kinesin (MCAK), the major functional antagonist of ch-TOG, which delocalizes from poles. ch-TOG is required for extrapole formation in prometaphases lacking Aurora-A, because co-depletion of Aurora-A and ch-TOG mitigates the fragmented pole phenotype. These results indicate a novel function of Aurora-A, the regulation of ch-TOG and MCAK localization, and highlight a common pathway involving the three factors in control of spindle pole integrity.

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References

  • Agnese V, Bazan V, Fiorentino FP, Fanale D, Badalamenti G, Colucci G et al. (2007). The role of Aurora-A inhibitors in cancer therapy. Ann Oncol 6: vi47–vi52.

    Google Scholar 

  • Anand S, Penrhyn-Lowe S, Venkitaraman AR . (2003). AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell 3: 51–62.

    Article  CAS  Google Scholar 

  • Andrews PD . (2005). Aurora kinases: shining lights on the therapeutic horizon? Oncogene 24: 5005–5015.

    Article  CAS  Google Scholar 

  • Barr AR, Gergely F . (2007). Aurora-A: the maker and breaker of spindle poles. J Cell Sci 120: 2987–2996.

    Article  CAS  Google Scholar 

  • Barros TP, Kinoshita K, Himan AA, Raff JW . (2005). Aurora-A activates D-TACC-Msps complexes exclusively at centrosomes to stabilize centrosomal microtubules. J Cell Biol 170: 1039–1046.

    Article  CAS  Google Scholar 

  • Blagden SP, Glover DM . (2003). Polar expeditions-provisioning the centrosome for mitosis. Nature Cell Biol 5: 505–511.

    Article  CAS  Google Scholar 

  • Cassimeris L, Morabito J . (2004). TOGp, the human homolog of XMAP215/Dis1, is required for centrosome integrity, spindle pole organisation, and bipolar spindle assembly. Mol Biol Cell 15: 1580–1590.

    Article  CAS  Google Scholar 

  • Ciciarello M, Mangiacasale R, Lavia P . (2007). Spatial control of mitosis by the GTPase Ran. Cell Mol Life Sci 64: 1891–1914.

    Article  CAS  Google Scholar 

  • De Luca M, Lavia P, Guarguaglini G . (2006). A functional interplay between Aurora-A, Plk1 and TPX2 at spindle poles: Plk1 controls centrosomal localization of Aurora-A and TPX2 spindle association. Cell Cycle 5: 296–303.

    Article  CAS  Google Scholar 

  • Doxsey S . (2001). Re-evaluating centrosome function. Nature 2: 688–698.

    CAS  Google Scholar 

  • Fielding AB, Dobreva I, McDonald PC, Foster LJ, Dedhar S . (2008). Integrin-linked kinase localizes to the centrosome and regulates mitotic spindle organization. J Cell Biol 180: 681–689.

    Article  CAS  Google Scholar 

  • Fukasawa K . (2006). Centrosome amplification, chromosome instability and cancer development. Cancer Lett 230: 6–19.

    Article  Google Scholar 

  • Gadde S, Heald R . (2004). Mechanism and molecules of the mitotic spindle. Curr Biol 14: 797–805.

    Article  Google Scholar 

  • Gard DL, Becker BE, Romney JS . (2004). MAPping the eukaryotic tree of life: structure, function, and evolution of the MAP215/Dis1 family of microtubule-associated proteins. Int Rev Cytol 239: 179–272.

    Article  CAS  Google Scholar 

  • Gergely F, Draviam VM, Raff JW . (2003). The ch-TOG/XMAP215 protein is essential for spindle pole organization in human somatic cells. Genes Dev 17: 336–341.

    Article  CAS  Google Scholar 

  • Giet R, McLean D, Descamps S, Lee MJ, Raff JW, Prigent C et al. (2002). Drosophila Aurora A kinase is required to localize D-TACC to centrosomes and to regulate astral microtubules. J Cell Biol 156: 437–451.

    Article  CAS  Google Scholar 

  • Giet R, Petretti C, Prigent C . (2005). Aurora kinases, aneuploidy and cancer, a coincidence or a real link? Trends Cell Biol 15: 241–250.

    Article  CAS  Google Scholar 

  • Hoar K, Chakravarty A, Rabino C, Wysong D, Bowman D, Roy N et al. (2007). MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy. Mol Cell Biol 27: 4513–4525.

    Article  CAS  Google Scholar 

  • Holmfeldt P, Zhang X, Stenmark S, Walczak CE, Gullberg M . (2005). CaMKIIgamma-mediated inactivation of the Kin I kinesin MCAK is essential for bipolar spindle formation. EMBO J 24: 1256–1266.

    Article  CAS  Google Scholar 

  • Kinoshita K, Noetzel TL, Pelletier L, Mechtler K, Drechsel DN, Schwager A et al. (2005). Aurora A phosphorylation of TACC3/maskin is required for centrosome dependent microtubule assembly in mitosis. J Cell Biol 170: 1047–1055.

    Article  CAS  Google Scholar 

  • Koffa MD, Casanova CM, Santarella R, Köcher T, Wilm M, Mattaj IW . (2006). HURP is part of a Ran-dependent complex involved in spindle formation. Curr Biol 16: 743–754.

    Article  CAS  Google Scholar 

  • Kops GJ, Weaver BAA, Cleveland DW . (2005). On the road to cancer: aneuploidy and the mitotic checkpoint. Nature Rev Cancer 5: 773–785.

    Article  CAS  Google Scholar 

  • Kufer TA, Sillje HH, Korner R, Gruss OJ, Meraldi P, Nigg EA . (2002). Human TPX2 is required for targeting Aurora-A kinase to the spindle. J Cell Biol 158: 617–623.

    Article  CAS  Google Scholar 

  • Lee MJ, Gergely F, Jeffers K, Peak-Chew SY, Raff JW . (2001). Msps/XMAP215 interacts with the centrosomal protein D-TACC to regulate microtubule behaviour. Nat Cell Biol 3: 643–649.

    Article  CAS  Google Scholar 

  • LeRoy PJ, Hunter JJ, Hoar KM, Burke KE, Shinde V, Ruan J et al. (2007). Localization of human TACC3 to mitotic spindles is mediated by phosphorylation on Ser558 by Aurora-A: a novel pharmacodynamic method for measuring Aurora A activity. Cancer Res 67: 5362–5370.

    Article  CAS  Google Scholar 

  • Luders J, Stearns T . (2007). Microtubule-organizing centres: a re-evaluation. Nat Rev Mol Cell Biol 8: 161–167.

    Article  Google Scholar 

  • Manning AL, Compton DA . (2007). Mechanisms of spindle-pole organization are influenced by kinetochore activity in mammalian cells. Curr Biol 17: 260–265.

    Article  CAS  Google Scholar 

  • Marumoto T, Honda S, Hara T, Nitta M, Hirota T, Kohmura E et al. (2003). Aurora-A kinase maintains the fidelity of early and late mitotic evens in HeLa cells. J Biol Chem 278: 51786–51795.

    Article  CAS  Google Scholar 

  • Marumoto T, Zhang D, Saya H . (2005). Aurora-A—a guardian of poles. Mol Cell Biol 5: 42–50.

    CAS  Google Scholar 

  • Meraldi P, Honda R, Nigg EA . (2002). Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53−/− cells. EMBO J 21: 483–492.

    Article  CAS  Google Scholar 

  • Nigg EA . (2006). Origins and consequences of centrosome aberrations in human cancers. Int J Cancer 119: 2717–2723.

    Article  CAS  Google Scholar 

  • Peset I, Seiler J, Sardon T, Bejarano LA, Rybina S, Vernos I . (2005). Function and regulation of Maskin, a TACC family protein, in microtubule growth during mitosis. J Cell Biol 170: 1057–1066.

    Article  CAS  Google Scholar 

  • Sharp DJ, Rogers GC, Scholey JM . (2000). Microtubule motors in mitosis. Nature 407: 41–47.

    Article  CAS  Google Scholar 

  • Weaver BA, Cleveland DW . (2005). Decoding the links between mitosis, cancer, and chemotherapy: the mitotic checkpoint, adaptation, and cell death. Cancer Cell 8: 7–12.

    Article  CAS  Google Scholar 

  • Weaver BA, Cleveland DW . (2006). Does aneuploidy cause cancer? Curr Opin Cell Biol 18: 658–667.

    Article  CAS  Google Scholar 

  • Zhang X, Ems-McClung SC, Walczak CE . (2008). Aurora A phosphorylates MCAK to control Ran-dependent spindle bipolarity. Mol Biol Cell 19: 2752–2765.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank M Ciciarello and R Mangiacasale for helpful discussions and JL Salisbury and C Walczak for reagents. This work was supported by AIRC (Italian Association for Cancer Research) grants (to PL).

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Authors and Affiliations

  1. Institute of Molecular Biology and Pathology, CNR, c/o University of Rome ‘La Sapienza’, Rome, Italy

    M De Luca, L Brunetto, I A Asteriti, M Giubettini, P Lavia & G Guarguaglini

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  1. M De Luca
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  2. L Brunetto
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  3. I A Asteriti
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  4. M Giubettini
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  5. P Lavia
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  6. G Guarguaglini
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Correspondence to G Guarguaglini.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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De Luca, M., Brunetto, L., Asteriti, I. et al. Aurora-A and ch-TOG act in a common pathway in control of spindle pole integrity. Oncogene 27, 6539–6549 (2008). https://doi.org/10.1038/onc.2008.252

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