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

Schneider, L; Eßmann, Frank; Kletke, Anja; Rı́o, Paula; Hanenberg, Helmut; Wetzel, Wiebke; Schulze‐Osthoff, Klaus; Nürnberg, Bernd; Piekorz, Roland P.

doi:10.1074/jbc.m704151200

Cited by 76 publications

(74 citation statements)

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“…Previous studies have shown that transforming acidic coiledcoil-containing protein 3 (TACC3) is essential for the mitotic spindle assembly and chromosome alignment, but the mechanism remains largely unknown (14)(15)(16)(17)(18). Here we reveal that TACC3-dependent small microtubule aster formation and sorting near the kinetochores contribute to correct microtubulekinetochore connections.…”

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confidence: 60%

Self-assembly and sorting of acentrosomal microtubules by TACC3 facilitate kinetochore capture during the mitotic spindle assembly

Chen

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Kinetochore capture by dynamic kinetochore microtubule fibers (K fibers) is essential for proper chromosome alignment and accurate distribution of the replicated genome during cell division. Although this capture process has been extensively studied, the mechanisms underlying the initiation of this process and the proper formation of the K fibers remain largely unknown. Here we show that transforming acidic coiled-coil-containing protein 3 (TACC3) is essential for kinetochore capture and proper K-fiber formation in HeLa cells. To observe the assembly of acentrosomal microtubules more clearly, the cells were released from higher concentrations of nocodazole into zero or lower concentrations. We find that small acentrosomal TACC3-microtubule aster formation near the kinetochores and binding of the asters with the kinetochores are the initial steps of the kinetochore capture by the acentrosomal microtubules, and that the sorting of kinetochore-captured acentrosomal microtubules with centrosomal microtubules leads to the capture of kinetochore by centrosomal microtubules from both spindle poles. We demonstrate that the sorting of the TACC3-associated microtubules with the centrosomal microtubules is a crucial process for spindle assembly and chromosome movement. These findings, which are also supported in the unperturbed mitosis without nocodazole, reveal a critical TACC3-dependent acentrosomal microtubule nucleation and sorting process to regulate kinetochore-microtubule connections and provide deep insight into the mechanisms of mitotic spindle assembly and chromosome alignment.T o ensure proper segregation of the chromosomes into its two daughter cells during proliferation, the chromosomes of a mother cell must be captured by its assembling mitotic spindle through attachment of the chromosome kinetochores and the dynamic spindle microtubules (1). A "search-and-capture" model was proposed long ago, in which the dynamic spindle microtubules nucleated from the centrosomes search for and capture the chromosome kinetochores (2). Previous studies showed that the kinetochores are initially captured by the spindle-polenucleated microtubules with their lateral side (3, 4). Once captured, the kinetochores with their chromosomes are transported along the microtubules toward a spindle pole, and the microtubules shrink at their plus ends until the establishment of the end-on attachment (4, 5). However, this model is insufficient to explain the initial connection of the kinetochore and the spindle microtubules in the centrosome-independent spindle assembly process. Recent studies in Xenopus extracts indicated that microtubules are nucleated near the chromosomes and self-organize into a spindle (6). A new model for acentrosomal spindle assembly has been raised in mouse oocytes, in which self-organized microtubule organizing centers (MTOCs) replace the centrosome function (7). The somatic cells may also use the centrosome-independent pathway for their spindle assembly (8-10). In Drosophila cells, the centrosome-independent assem...

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confidence: 60%

Self-assembly and sorting of acentrosomal microtubules by TACC3 facilitate kinetochore capture during the mitotic spindle assembly

Chen

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…We compared cellular stress responses of MCF-7 and MCF-7/caspase-3 cells toward treatments that interfere with microtubule assembly, such as the drug PTX and depletion of TACC3 that was achieved via an inducible RNA interference approach (Schneider et al, 2007). Both cell lines were engineered to express control or TACC3-specific shRNAs upon doxycycline (DOX) treatment (Supplementary Material & Methods).…”

Section: Resultsmentioning

confidence: 99%

“…TACC proteins are evolutionarily conserved and regulate centrosome integrity, centrosome-dependent assembly of microtubules and spindle stability during mitosis (Gergely et al, 2003;Cassimeris and Morabito, 2004;Schneider et al, 2007;Yao et al, 2007). Thereby, TACC3 is predominantly expressed during the G 2 /M phase of the cell cycle, where it localizes to the centrosome and spindle apparatus (Piekorz et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, we have recently shown that the cellular outcome of mitotic stress induced by TACC3 depletion is decisively determined by the status of the post-mitotic G 1 checkpoint. Whereas TACC3-deficient murine fibroblasts with functional post-mitotic checkpoints enter a reversible G 1 and G 2 arrest, checkpointcompromised cells rapidly succumb to mitotic cell death and polyploidization (Schneider et al, 2007(Schneider et al, , 2008. Given that centrosomal localization of human TACC3 requires its phosphorylation by Aurora A kinase at Ser558 (LeRoy et al, 2007) and because pharmacological inhibition of Aurora A kinase induces premature senescence (Huck et al, 2010), we explored here (i) whether senescence is the prevailing outcome of TACC3 reduction in G 1 checkpoint-proficient transformed and non-transformed breast epithelial cells and (ii) to which extent their chemosensitivity against PTX can be modulated by targeting TACC3 expression.…”

Section: Introductionmentioning

confidence: 99%

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The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

et al. 2010

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Microtubule-interfering cancer drugs such as paclitaxel (PTX) often cause chemoresistance and severe side effects, including neurotoxicity. To explore potentially novel antineoplastic molecular targets, we investigated the cellular response of breast carcinoma cells to short hairpin(sh)RNA-mediated depletion of the centrosomal protein transforming acidic coiled coil (TACC) 3, an Aurora A kinase target expressed during mitosis. Unlike PTX, knockdown of TACC3 did not trigger a cell death response, but instead resulted in a progressive loss of the pro-apoptotic Bcl-2 protein Bim that links microtubule integrity to spindle poison-induced cell death. Interestingly, TACC3-depleted cells arrested in G 1 through a cellular senescence program characterized by the upregulation of nuclear p21 WAF , downregulation of the retinoblastoma protein and extracellular signal-regulated kinase 1/2, formation of HP1c (phospho-Ser83)-positive senescence-associated heterochromatic foci and increased senescence-associated b-galactosidase activity. Remarkably, the onset of senescence following TACC3 knockdown was strongly accelerated in the presence of non-toxic PTX concentrations. Thus, we conclude that mitotic spindle stress is a major trigger of premature senescence and propose that the combined targeting of the centrosomal Aurora A-TACC3 axis together with drugs interfering with microtubule dynamics may efficiently improve the chemosensitivity of cancer cells.

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“…Depletion of TACC3 by RNAi leads to chromosome misalignment and reduced localization of kinetochore proteins in mitosis, suggesting that TACC3 is required for microtubule-kinetochore interaction [26,29]. Meanwhile, clathrin was also found to be required for chromo- The 'clathrin recruits TACC3′ model.…”

Section: Clathrin Regulates Mitotic Chromosome Alignmentmentioning

confidence: 99%

Novel functions of endocytic player clathrin in mitosis

Jiang

Zhang

2011

Cell Res

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Clathrin has been widely recognized as a pivotal player in endocytosis, in which several adaptors and accessory proteins are involved. Recent studies suggested that clathrin is also essential for cell division. Here this review mainly focuses on the clathrin-dependent mechanisms involved in spindle assembly and chromosome alignment. In mitosis, clathrin forms a complex with phosphorylated TACC3 to ensure spindle stability and proper chromosome alignment. The clathrin-regulated mechanism in mitosis requires the crosstalk among clathrin, spindle assembly factors (SAFs), Ran-GTP and mitotic kinases. Meanwhile, a coordinated mechanism is required for role transitions of clathrin during endocytosis and mitosis. Taken together, the findings of the multiple functions of clathrin besides endocytosis have expanded our understanding of the basic cellular activities.

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

Cited by 76 publications

References 59 publications

Self-assembly and sorting of acentrosomal microtubules by TACC3 facilitate kinetochore capture during the mitotic spindle assembly

Self-assembly and sorting of acentrosomal microtubules by TACC3 facilitate kinetochore capture during the mitotic spindle assembly

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

Novel functions of endocytic player clathrin in mitosis

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