Chromosome-induced microtubule assembly mediated by TPX2 is required for spindle formation in HeLa cells

Gruß, Oliver J.; Wittmann, Malte; Yokoyama, Hideki; Pepperkok, Rainer; Kufer, Thomas A.; Silljé, Herman H W; Karsenti, Eric; Mattaj, Iain W.; Vernos, Isabelle

doi:10.1038/ncb870

Cited by 298 publications

(340 citation statements)

References 37 publications

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“…These are molecules of the chromosomal passenger complex (CDCA8 and Aurora kinase B; ref. 34 37,38), and several members of the kinesin superfamily of mitotic motor proteins involved in spindle function and cytokinesis (KIFC1, KIF23, KIF11, and KNSL7; refs. 39 -45).…”

Section: Discussionmentioning

confidence: 99%

Expression of Late Cell Cycle Genes and an Increased Proliferative Capacity Characterize Very Early Relapse of Childhood Acute Lymphoblastic Leukemia

Kirschner-Schwabe

Lottaz

Tödling

et al. 2006

Clinical Cancer Research

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Purpose: In childhood acute lymphoblastic leukemia (ALL), f25% of patients suffer from relapse. In recurrent disease, despite intensified therapy, overall cure rates of 40% remain unsatisfactory and survival rates are particularly poor in certain subgroups. The probability of long-term survival after relapse is predicted from well-established prognostic factors (i.e., time and site of relapse, immunophenotype, and minimal residual disease). However, the underlying biological determinants of these prognostic factors remain poorly understood. Experimental Design: Aiming at identifying molecular pathways associated with these clinically well-defined prognostic factors, we did gene expression profiling on 60 prospectively collected samples of first relapse patients enrolled on the relapse trial ALL-REZ BFM 2002 of the Berlin-Frankfurt-Mu« nster study group. Results: We show here that patients with very early relapse of ALL are characterized by a distinctive gene expression pattern.We identified a set of 83 genes differentially expressed in very early relapsed ALL compared with late relapsed disease. The vast majority of genes were up-regulated and many were late cell cycle genes with a function in mitosis. In addition, samples from patients with very early relapse showed a significant increase in the percentage of S and G 2 -M phase cells and this correlated well with the expression level of cell cycle genes. Conclusions: Very early relapse of ALL is characterized by an increased proliferative capacity of leukemic blasts and up-regulated mitotic genes.The latter suggests that novel drugs, targeting late cell cycle proteins, might be beneficial for these patients that typically face a dismal prognosis.Acute lymphoblastic leukemia (ALL) is the most common malignant disease in children (1). Although event-free survival rates range between 70% and 75%, relapse of ALL remains the fourth most frequent diagnosis in childhood cancer affecting 25% of ALL patients (2). At relapse, overall cure rates of f40% remain unsatisfactory and survival rates are particularly poor in certain subgroups (3). Treatment of relapse usually implies intensified polychemotherapy containing high-dose elements. Although in most children, second remissions can be induced high-risk patients require further treatment intensification by stem cell transplantation. Stem cell transplantation provides a better relapse-free survival rate than chemotherapy alone but is also associated with higher treatment-related morbidity and mortality rates (2). Thus, alternative treatment strategies are needed to improve the treatment and outcome of patients with relapsed ALL.In the treatment of ALL relapse, intensity of chemotherapy and stem cell transplantation are indicated by well-established prognostic factors (summarized in ref.2), with the most evident being the time to relapse. Early recurrence of disease with respect to frontline therapy affects f60% of patients and is associated with a high rate of nonresponse to treatment, shorter duration of second ...

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Section: Discussionmentioning

confidence: 99%

Expression of Late Cell Cycle Genes and an Increased Proliferative Capacity Characterize Very Early Relapse of Childhood Acute Lymphoblastic Leukemia

Kirschner-Schwabe

Lottaz

Tödling

et al. 2006

Clinical Cancer Research

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“…It has been demonstrated that TPX2 overexpression induces the amplification of centrosomes and results in DNA polyploidy (9). TPX2 also serves a crucial role in the proliferation of various tumor cells (10,11).…”

Section: Introductionmentioning

confidence: 99%

“…TPX2 also serves a crucial role in the proliferation of various tumor cells (10,11). TPX2 expression is closely regulated by the cell cycle, and exhibits particularly high expression in proliferating cells transitioning between the G 1 and S phase (12)(13)(14). Certain studies have demonstrated that the TPX2 gene, in addition to elevated gene copy numbers, is frequently identified in various human malignancies, including lung carcinoma (15), salivary gland cancer (16), esophageal cell carcinoma (17) and breast cancer (18).…”

Section: Introductionmentioning

confidence: 99%

TPX2 in human clear cell renal carcinoma: Expression, function and prognostic significance

et al. 2016

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Abstract. Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated protein. TPX2 is considered to be an important gene in tumorigenesis; however, the particular function of TPX2 in the development of human renal cell carcinoma (RCC) is unknown. In the present study, the expression, function and prognostic significance of TPX2 in human RCC was analyzed. A total of 286 tissue samples from patients with RCC who had undergone nephrectomies were utilized. Subsequently, the expression of TPX2 protein was investigated using immunohistochemistry and western blotting, and TPX2 mRNA expression was examined using reverse transcription-quantitative polymerase chain reaction. To establish the effect of TPX2 on the proliferation and invasion of the RCC cells, TPX2 expression was increased by stable transfection with a TPX2 vector and TPX2 expression was decreased using small interfering RNA. Proliferation of the RCC cells was analyzed using a WST-1 assay and an animal xenograft model with BALB/c nude mice, whilst invasion of the RCC cells was examined using a Matrigel-coated invasion chamber. It was demonstrated that TPX2 expression was significantly higher in the RCC tissues compared with normal kidney tissues (P<0.05). Furthermore, TPX2 expression was associated with tumor size, histological grade and tumor stage (P<0.05), and was observed to markedly increase the proliferation and invasion of the RCC cells. It may be concluded that the expression of TPX2 is significantly upregulated in RCC tissue, subsequently increasing the proliferative and invasive ability of RCC cells. Therefore, the protein may serve as a therapeutic target and independent prognostic factor in the treatment of human RCC.

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“…A third possibility is that there are new MTs that grow from the chromosomes and become incorporated into the K-fiber bundles (Khodjakov et al, 2003). The MTs that grow from the chromosomes may quickly become coated with HURP or with TPX2, two specialized MT-associated proteins that have been implicated in chromosomemediated spindle assembly (Gruss et al, 2002;Koffa et al, 2006;Sillje et al, 2006;Tulu et al, 2006;Wong and Fang, 2006;Casanova et al, 2008), such that their overall dynamics are more consistent with the stabilized MTs present in a K-fiber. This possibility is consistent with our observation in Figure 5, G and H, where as the concentration of paclitaxel is increased, the percentage of MTs in the slow phase is increased.…”

Section: Control Of Kinetochore Mt Dynamicsmentioning

confidence: 99%

MCAK and Paclitaxel Have Differential Effects on Spindle Microtubule Organization and Dynamics

Rizk

Bohannon

Wetzel

et al. 2009

MBoC

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Within the mitotic spindle, there are multiple populations of microtubules with different turnover dynamics, but how these different dynamics are maintained is not fully understood. MCAK is a member of the kinesin-13 family of microtubule-destabilizing enzymes that is required for proper establishment and maintenance of the spindle. Using quantitative immunofluorescence and fluorescence recovery after photobleaching, we compared the differences in spindle organization caused by global suppression of microtubule dynamics, by treating cells with low levels of paclitaxel, versus specific perturbation of spindle microtubule subsets by MCAK inhibition. Paclitaxel treatment caused a disruption in spindle microtubule organization marked by a significant increase in microtubules near the poles and a reduction in K-fiber fluorescence intensity. This was correlated with a faster t 1/2 of both spindle and K-fiber microtubules. In contrast, MCAK inhibition caused a dramatic reorganization of spindle microtubules with a significant increase in astral microtubules and reduction in K-fiber fluorescence intensity, which correlated with a slower t 1/2 of K-fibers but no change in the t 1/2 of spindle microtubules. Our data support the model that MCAK perturbs spindle organization by acting preferentially on a subset of microtubules, and they support the overall hypothesis that microtubule dynamics is differentially regulated in the spindle. INTRODUCTIONThe cytoskeleton must undergo dramatic reorganization as cells transition from interphase to mitosis to assemble the mitotic spindle. The spindle is a macromolecular structure composed of a dynamic array of microtubules (MTs) and their associated proteins that is necessary for proper chromosome segregation (Compton, 2000;Walczak and Heald, 2008). At the onset of mitosis, there is an increase in MT turnover that allows for breakdown of the interphase array and assembly of the mitotic spindle (Saxton et al., 1984;. This change is correlated with an increased catastrophe frequency (transition from growth to shrinkage) and a decreased rescue frequency (transition from shrinkage to growth) (Belmont et al., 1990;Gliksman et al., 1992;Verde et al., 1992;Rusan et al., 2001). The changes in MT dynamics are also correlated with a change in MT polymer levels during mitosis (Zhai et al., 1996). At nuclear envelope breakdown, there is a dramatic decrease in MT polymer levels, which may allow the cell to rapidly assemble a mitotic spindle because the released tubulin dimers can polymerize into new spindle MTs. As the cell progresses from mitosis to the next interphase, there is no change in the levels of MT polymer (Zhai et al., 1996), suggesting that MT polymer gets reorganized to reform the interphase MT cytoskeleton, without a significant change in the dynamics of the MTs. These studies highlight the need for the cell to possess a mechanism to temporally regulate MT dynamics.In addition to the temporal changes in dynamics throughout the cell cycle, the dynamics of MTs within mitosis are also...

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Chromosome-induced microtubule assembly mediated by TPX2 is required for spindle formation in HeLa cells

Cited by 298 publications

References 37 publications

Expression of Late Cell Cycle Genes and an Increased Proliferative Capacity Characterize Very Early Relapse of Childhood Acute Lymphoblastic Leukemia

Expression of Late Cell Cycle Genes and an Increased Proliferative Capacity Characterize Very Early Relapse of Childhood Acute Lymphoblastic Leukemia

TPX2 in human clear cell renal carcinoma: Expression, function and prognostic significance

MCAK and Paclitaxel Have Differential Effects on Spindle Microtubule Organization and Dynamics

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