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J. Biol. Chem., Vol. 282, Issue 40, 29273-29283, October 5, 2007

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The Transforming Acidic Coiled Coil 3 Protein Is Essential for Spindle-dependent Chromosome Alignment and Mitotic Survival^*

Leonid Schneider, Frank Essmann, Anja Kletke, Paula Rio^¶1, Helmut Hanenberg^¶||, Wiebke Wetzel, Klaus Schulze-Osthoff, Bernd Nürnberg, and Roland P. Piekorz²

From the Institut für Biochemie und Molekularbiologie II, Institut für Molekulare Medizin, ^¶Klinik für Kinder-Onkologie, -Hämatologie und -Klinische Immunologie, Universitätsklinikum der Heinrich-Heine-Universität, 40225 Düsseldorf, Germany and the ^||Department of Pediatrics, Wells Center for Pediatric Research, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana 46223

Cancer-associated centrosomal transforming acidic coiled coil (TACC) proteins are involved in mitotic spindle function. By employing gene targeting, we have recently described a nonredundant and essential role of TACC3 in regulating cell proliferation. In this study, we used an inducible RNA interference approach to characterize the molecular function of TACC3 and its role in mitotic progression and cell survival. Our data demonstrate that a TACC3 knockdown arrests G₁ checkpoint-compromised HeLa cells prior to anaphase with aberrant spindle morphology and severely misaligned chromosomes. Interestingly, TACC3-depleted cells fail to accumulate the mitotic kinase Aurora B and the checkpoint protein BubR1 to normal levels at kinetochores. Moreover, localization of the structural protein Ndc80 at outer kinetochores is reduced, indicating a defective kinetochore-microtubule attachment in TACC3-deficient cells. As a consequence of prolonged TACC3 depletion, cells undergo caspase-dependent cell death that relies on a spindle checkpoint-dependent mitotic arrest. TACC3 knockdown cells that escape from this arrest by mitotic slippage become highly polyploid and accumulate supernumerary centrosomes. Similarly, deficiency of the post-mitotic cell cycle inhibitor p21^WAF exacerbates the effects of TACC3 depletion. Our findings therefore point to an essential role of TACC3 in spindle assembly and cellular survival and identify TACC3 as a potential therapeutic target in cancer cells.

Received for publication, May 21, 2007 , and in revised form, July 27, 2007.

^* This work was supported by the Medical Faculty of the Heinrich-Heine-University Düsseldorf Intramural Grant 9772210 (to R. P. P.), Collaborative Research Center Grant SFB 728 of the German Research Foundation (to R. P. P.), German Research Foundation grants (to H. H., K. S. O., and B. N.), and the German Jose Carreras Foundation (to H. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1S and Figs. 1S–5S.

¹ Present address: Hematopoietic Gene Therapy Program, Centro de Investigaciones Energeticas, Medioambientales y Technologicas, Madrid, Spain.

² To whom correspondence should be addressed. Tel.: 49-211-81-12739; Fax: 49-211-81-12726; E-mail: Roland.Piekorz{at}uni-duesseldorf.de.

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