The transforming acidic coiled coil 3 protein is essential for spindle-dependent chromosome alignment and mitotic survival.
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 G(1) 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.
Schneider
Leonid
L
Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität, 40225 Düsseldorf, Germany.
Essmann
Frank
F
Kletke
Anja
A
Rio
Paula
P
Hanenberg
Helmut
H
Wetzel
Wiebke
W
Schulze-Osthoff
Klaus
K
Nürnberg
Bernd
B
Piekorz
Roland P
RP
D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002875:Chromosomes / Q000648:ultrastructure*; D003001:Cloning, Molecular; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000378:metabolism / Q000502:physiology*; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis; D034622:RNA Interference; D008941:Spindle Apparatus
D008869:Microtubule-Associated Proteins; C120551:TACC3 protein, human