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, Helmut Hanenberg, Wiebke Wetzel, Klaus Schulze-Osthoff, Bernd Nürnberg, Roland P. Piekorz

Research output: Contribution to journalArticle

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Abstract

Cancer-associated centrosomal transforming acidic coiled coil (TACC) proteins are involved in mitotic spindle function. By employing gene targeting, we have recently described a non-redundant 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 p21WAF 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.

Original languageEnglish
Pages (from-to)29273-29283
Number of pages11
JournalJournal of Biological Chemistry
Volume282
Issue number40
DOIs
StatePublished - Oct 5 2007

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Chromosomes
Kinetochores
Cells
Aurora Kinase B
Proteins
Cell proliferation
Cell death
Caspases
M Phase Cell Cycle Checkpoints
Genes
Centrosome
Anaphase
Spindle Apparatus
Polyploidy
RNA
Gene Targeting
RNA Interference
HeLa Cells
Microtubules
Neoplasms

ASJC Scopus subject areas

  • Biochemistry

Cite this

Schneider, L., Essmann, F., Kletke, A., Rio, P., Hanenberg, H., Wetzel, W., ... Piekorz, R. P. (2007). The transforming acidic coiled coil 3 protein is essential for spindle-dependent chromosome alignment and mitotic survival. Journal of Biological Chemistry, 282(40), 29273-29283. https://doi.org/10.1074/jbc.M704151200

The transforming acidic coiled coil 3 protein is essential for spindle-dependent chromosome alignment and mitotic survival. / Schneider, Leonid; Essmann, Frank; Kletke, Anja; Rio, Paula; Hanenberg, Helmut; Wetzel, Wiebke; Schulze-Osthoff, Klaus; Nürnberg, Bernd; Piekorz, Roland P.

In: Journal of Biological Chemistry, Vol. 282, No. 40, 05.10.2007, p. 29273-29283.

Research output: Contribution to journalArticle

Schneider, L, Essmann, F, Kletke, A, Rio, P, Hanenberg, H, Wetzel, W, Schulze-Osthoff, K, Nürnberg, B & Piekorz, RP 2007, 'The transforming acidic coiled coil 3 protein is essential for spindle-dependent chromosome alignment and mitotic survival', Journal of Biological Chemistry, vol. 282, no. 40, pp. 29273-29283. https://doi.org/10.1074/jbc.M704151200
Schneider, Leonid ; Essmann, Frank ; Kletke, Anja ; Rio, Paula ; Hanenberg, Helmut ; Wetzel, Wiebke ; Schulze-Osthoff, Klaus ; Nürnberg, Bernd ; Piekorz, Roland P. / The transforming acidic coiled coil 3 protein is essential for spindle-dependent chromosome alignment and mitotic survival. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 40. pp. 29273-29283.
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