Transient defects of mitotic spindle geometry and chromosome segregation errors
© Silkworth and Cimini; licensee BioMed Central Ltd. 2012
Received: 20 July 2012
Accepted: 24 July 2012
Published: 11 August 2012
Assembly of a bipolar mitotic spindle is essential to ensure accurate chromosome segregation and prevent aneuploidy, and severe mitotic spindle defects are typically associated with cell death. Recent studies have shown that mitotic spindles with initial geometric defects can undergo specific rearrangements so the cell can complete mitosis with a bipolar spindle and undergo bipolar chromosome segregation, thus preventing the risk of cell death associated with abnormal spindle structure. Although this may appear as an advantageous strategy, transient defects in spindle geometry may be even more threatening to a cell population or organism than permanent spindle defects. Indeed, transient spindle geometry defects cause high rates of chromosome mis-segregation and aneuploidy. In this review, we summarize our current knowledge on two specific types of transient spindle geometry defects (transient multipolarity and incomplete spindle pole separation) and describe how these mechanisms cause chromosome mis-segregation and aneuploidy. Finally, we discuss how these transient spindle defects may specifically contribute to the chromosomal instability observed in cancer cells.
KeywordsMitosis Mitotic spindle Kinetochore Centrosome Chromosomal instability Cancer Aneuploidy
Spindle Assembly Checkpoint
Nuclear Envelope Breakdown
Abnormal mitotic spindle geometry: permanent vs. transient
The bipolar geometry of the mitotic spindle is essential for accurate chromosome segregation, and already a century ago Theodor Boveri postulated that supernumerary centrosomes could lead to the production of aneuploid cells [23, 24]. Observations of mitosis in both transformed and non-transformed cells reveal that multipolar mitotic spindles do occasionally form [25–31]. Typically, chromosomes within multipolar spindles form metaphase plates that display branched, Y-, V-, or T-shaped configurations as a consequence of chromosome alignment between multiple spindle poles [25, 26]. Although chromosomes can align between supernumerary spindle poles, multipolar cell division has been shown to cause cell death in the progeny , most likely due to the fact that it causes massive chromosome mis-segregation, thus producing daughter cells that have far fewer chromosomes than is needed for survival. Moreover, anaphase lagging chromosomes (chromosomes that lag behind while all the other chromosomes segregate to the spindle poles during anaphase) are also frequently observed during multipolar cell division [25, 27], thus adding to the burden of chromosome mis-segregation in multipolar cell division. Given the risk, it is not surprising that multipolar spindle assembly is a rare event in non-transformed cells growing under optimal conditions. Conversely, multipolar spindle assembly is very common in cancer cells [28–30, 33–38], yet cancer cells avoid multipolar cell division and subsequent cell death by exploiting a number of mechanisms that allow centrosome clustering prior to anaphase onset [32, 39–41]. Microtubule-associated proteins (e.g., NuMA, TPX2, ch-TOG, and ARL2), motor proteins (e.g., dynein and HSET), central spindle components, CLASPs, components of the Augmin complex, anillin, proteins involved in sister chromatid cohesion, kinetochore components, and chromosomal passenger proteins have all been implicated in the clustering of centrosomes prior to chromosome segregation [40–45]. The molecular and structural requirements that cause some cells to undergo multipolar anaphase and others to cluster their centrosomes are not yet know. However, variations in expression levels of minus end directed motors that oppose motors which serve to separate the centrosomes are likely involved. Alternatively, the orientation of the centrosomes as well as their distance from one another may serve to facilitate supernumerary centrosome clustering. These possibilities have yet to be explored, but studies investigating these issues would undoubtedly lead to a more comprehensive understanding of the specific mechanism(s) responsible for centrosome clustering. Regardless of the specific mechanisms, however, it is clear that cancer cells employ strategies to avoid permanent multipolarity, thus experiencing this mitotic spindle defect only transiently.
Another type of abnormal spindle geometry is observed in prometaphase cells with unseparated or incompletely separated spindle poles. In these cells, the centrosomes fail to migrate to opposing positions around the nucleus (a process driven by dynein and kinesin-5; reviewed in ) before the cell enters prometaphase (i.e., before nuclear envelope breakdown, NEB). If the centrosomes persisted in such unseparated/partially separated configuration, the cell would arrest in mitosis with a monopolar spindle, which would then lead to either mitotic slippage or cell death [47–49]. However, all cell types studied to date appear capable of completing centrosome separation after NEB thanks to a number of mechanisms, including Eg5 motor activity [46, 50], myosin activity at the cell cortex [50, 51], and kinetochore/kinetochore-microtubule-generated forces [52, 53]. Once again, cells seem to have developed ways to avoid a permanent spindle defect and to limit monopolarity to a transient stage. The phenomenon of incomplete centrosome separation at NEB has been observed in a variety of cell types [52, 54–56] and, while it was initially described in the mid- 1970s [55, 56], only sporadic reports described this centrosome behavior over a period of several decades [51, 54]. Recently, this phenomenon has received renewed attention [53, 57] in part due to its correlation with increased rates of chromosome mis-segregation [57, 58]. Why in some cells the centrosomes can reach diametrically opposing positions around the nucleus prior to NEB, whereas in other cells they cannot, is not clear. However, it has been proposed that the cause may be a lack of coordination between the timing of NEB and centrosome separation [55–57]. In any case, these cells achieve complete centrosome separation after NEB with no noticeable defects in subsequent mitotic spindle assembly or in the timing of mitosis as defined by the time between NEB and anaphase onset [52, 55, 57–59]. Nevertheless, cells that complete centrosome separation after NEB will experience monopolarity or near-monopolarity (spindle geometry defect) over a time window in early prometaphase, when initial kinetochore-microtubule attachments are being established.
Transient spindle geometry defects, kinetochore mis-attachments, and aneuploidy
Studies in various types of cancer cells showed that multipolar prometaphase cells display higher numbers of merotelic kinetochore attachments (one kinetochore bound to microtubules from two spindle poles instead of just one) compared to bipolar prometaphases ([32, 39]; Figure 2A). Moreover, both experimental and computational analysis showed that the number of merotelic kinetochores increases with increasing numbers of spindle poles . To explain this correlation, it was proposed that the reduced distance between each pair of spindle poles would increase the likelihood of each kinetochore to be reached by and bind to microtubules from two spindle poles instead of just one [32, 39].
Experimental and computational studies were also employed to investigate the process of establishment of kinetochore attachment in cells with incomplete centrosome separation at NEB. These studies showed that when the two spindle poles are very close to each other upon NEB, chromosomes are extremely likely to establish syntelic attachments (both sister kinetochores bound to microtubules from the same spindle pole) (; Figure 2B, top). As the spindle poles separate, such syntelic attachments can be partially corrected and converted into merotelic attachments (; Figure 2B, top). When, upon NEB, the spindle poles are farther apart, but not diametrically opposed, kinetochores can form merotelic attachments without transitioning through a syntelic intermediate (; Figure 2B, bottom). What is important to emphasize here is that in both cases of spindle geometry defects (multipolarity and near-monopolarity), large numbers of merotelic kinetochores are formed before spindle bi-polarization (Figure 2). Because the SAC cannot detect merotelic kinetochore attachment [61–65], cells can progress through mitosis in the presence of large numbers of merotelic kinetochores. Although merotelic kinetochores can be corrected by an Aurora B-dependent mechanism [66, 67], mitosis will not halt to allow for correction, and therefore high rates of merotelic kinetochore formation invariably result in high rates of anaphase lagging chromosomes (reviewed in ). Indeed, both transient multipolarity and incomplete spindle pole separation have been shown to result in high rates of anaphase lagging chromosomes ([32, 39, 58]; Figure 2). Thus, abnormal spindle geometry, albeit transient, can have detrimental effects on the fidelity of chromosome segregation, and represents a potential source of aneuploidy. Interestingly, over 70% of cancer cells from various sites are aneuploid [21, 68], and many of them also display high rates of chromosome mis-segregation, a phenotype that leads to continuous changes in chromosome number, or c hromosomal in stability (CIN) [22, 69–71]. Recent studies have shown that merotelically attached anaphase lagging chromosomes represent the most common chromosome segregation defect in CIN cancer cells [32, 39, 72]. One cause of such high rates of anaphase lagging chromosomes appears to be the inefficiency of the correction mechanisms for kinetochore mis-attachments in cancer cells . However, the high rates at which kinetochore mis-attachments (particularly merotelic) form are perhaps the major cause of chromosome mis-segregation in cancer cells, and the transient spindle geometry defects described above represent the most likely mechanisms of kinetochore mis-attachment formation in cancer cells ([32, 39]; Silkworth, Nardi, and Cimini, unpublished; see below for further discussion).
Transient spindle geometry defects in development, adult tissues, and cancer
The transient spindle geometry defects described here and their effects on the fidelity of chromosome segregation have been mainly characterized in tissue culture cells, with transient multipolarity exclusively observed in CIN cancer cells to date. Indeed, the frequencies of multipolar spindles in non-transformed or non-CIN cancer cells are typically very low (Silkworth, Nardi, and Cimini, unpublished). Given the causal relation between transient multipolarity and chromosome mis-segregation and that transient multipolarity is very common in CIN cancer cells, this mechanism is widely recognized as a major player in CIN. Whether this mechanism is also acting in tumors in situ has not been investigated. However, multipolar spindles have been observed in tumor tissues [74–76] and short-term tumor cell cultures [77, 78].
Although incomplete spindle pole separation at NEB has also been characterized mainly in tissue culture cells, the information available to date reveals that this mechanism is not exclusive to cancer cells, and has indeed been observed in several different types of tissue culture cells at frequencies of ~40-45% [51, 52, 55, 57, 59]. Moreover, studies aimed at investigating various aspects of cell division provide useful information on the occurrence and relevance of this mechanism in contexts other than tissue culture. For example, in both the one- and two-cell stage of the Caenorhabditis elegans embryo, the centrosomes achieve opposing positions around the nucleus before the nuclear envelope breaks down . Similarly, in the syncytial Drosophila embryo, the centrosomes always achieve diametric arrangement around prophase nuclei , and the nuclear envelope does not break down until the centrosomes have completed their movement around the nucleus . This ability of cells in developing embryos to completely separate their centrosomes before NEB has also been observed in Drosophila melanogaster neurogenesis. Indeed, in both epidermoblasts and neuroblasts the centrosomes are completely separated before the onset of prometaphase . Given the risk of chromosome mis-segregation associated with incomplete centrosome separation at NEB, it is not surprising that this defect is not observed during early development, as it would potentially lead to mosaic aneuploidy and possibly embryonic death.
The incidence of incomplete centrosome separation at NEB in normal adult tissues has not been investigated to date. However, a recent study showed that non-cancer RPE1 cells, which are known to maintain a stable karyotype with negligible rates of aneuploidy , always succeed to separate their centrosomes before NEB . This observation suggests that centrosome separation in normal proliferating cells, like in developing embryo cells, may be better timed with NEB compared to cancer cells or certain stabilized tissue culture cells.
The open question, then, is whether incomplete centrosome separation at NEB may play a role in cancer cell CIN, and if so, to what extent. As discussed above, transient multipolarity is recognized as a major cause of chromosome mis-segregation in cancer cells [32, 39, 84]. However, some CIN cancer cell types cannot cluster the centrosomes of multipolar spindles very efficiently (Silkworth, Nardi, and Cimini, unpublished). Yet, these cells exhibit high rates of chromosome mis-segregation in the form of lagging chromosomes in bipolar anaphase cells (Silkworth, Nardi, and Cimini, unpublished), raising the possibility that incomplete spindle pole separation at NEB may play a role in promoting formation of kinetochore mis-attachments in these cells. Analysis of centrosome separation in early prometaphase shows that incomplete spindle pole separation at NEB can be observed in as many as 70% of the cells in those cancer cell lines that display inefficient centrosome clustering (Silkworth, Nardi, and Cimini, unpublished). These observations indicate that incomplete centrosome separation at NEB may play an important role in promoting CIN in certain cancer types.
Accurate partitioning of chromosomes to the daughter cells during mitosis is of utmost importance to ensure development and growth of all eukaryotic organisms. Defects of the mitotic spindle have a dramatic impact on chromosome segregation. However, the effect on the cell population can be even more dramatic if the spindle defects are only transient. Indeed, whereas permanent spindle defects typically lead to cell death in the progeny, transient spindle defects increase the rates of chromosome mis-segregation, but not to a level that would affect cell viability, thus ultimately being more threatening to the overall cell population and/or the organism. Here, we have discussed two types of transient mitotic spindle defects that are associated with increased rates of kinetochore mis-attachment formation and chromosome mis-segregation. One of them, transient multipolarity, is currently recognized as a common mechanism of CIN in cancer cells [32, 39, 84]. Conversely, the incomplete centrosome separation (at NEB) mechanism appears to occur at moderate levels in many different types of cancer cells, but it also occurs at very high frequencies in cells from certain types of cancers. This is a very interesting observation that needs further investigation. For example, it would be interesting to study whether the incidence of this mechanism relates to cancer progression or whether it is typical of cancer cells from specific sites. Moreover, the fact that incomplete centrosome separation at NEB is also observed in several non-transformed cell types suggests the possibility that this mechanism may occur in normal proliferating somatic cells and may, through its ability to promote chromosome mis-segregation, play a role in tumor initiation. This possibility undoubtedly deserves consideration in the near future. Future studies should also be focused on the causes of incomplete centrosome separation at NEB. It is plausible to imagine that mis-regulation of key motor proteins may be at the basis of this defect. An alternative hypothesis is that the ability of the centrosomes to separate in a timely fashion is dictated by signals from and/or physical interactions with trans-membrane elements. For example, it is widely acknowledged that dividing cells within polarized epithelia rely on such mechanisms to orient the mitotic spindle [85–87]. Similar mechanisms may dictate not only the exact positioning of the centrosomes, but also the timing of centrosome separation. One last possibility is that centrosome separation per se is not impaired in cells with incomplete centrosome separation at NEB, but the exact timing is inaccurate, so that centrosome separation and NEB are no longer coordinated. It is possible that such coordination is finely regulated at the early stages of development [50, 80, 81, 88], but is lost in the adult. In fact, optimal timing between centrosome separation, NEB, and chromosome segregation is very important during the early stages of development to ensure the chromosomal stability necessary to the development of a healthy adult organism. In conclusion, incomplete centrosome separation at NEB is a newly characterized mechanism of CIN for which we still have numerous open questions, and as such it will likely become the focus of many studies in the near future.
WTS was a PhD student in the Department of Biological Sciences at Virginia Tech, and completed his dissertation work in July 2012 under the guidance of Dr. Daniela Cimini.
DC is an Associate Professor in the Department of Biological Sciences at Virginia Tech.
We would like to thank the members of the Cimini lab for helpful discussion and feedback. Work in the Cimini lab is supported by NSF grant MCB-0842551 and HFSP grant RGY0069/2010.
- Flemming W: Zellsubstanz, Kern und Zelltheilung. Leipzig: F.C.W. Vogel; 1882.
- Paweletz N: Walther Flemming: pioneer of mitosis research. Nat Rev Mol Cell Biol 2001,2(1):72–75. 10.1038/35048077View ArticlePubMed
- Rieder CL, Khodjakov A: Mitosis through the microscope: advances in seeing inside live dividing cells. Science 2003,300(5616):91–96. 10.1126/science.1082177View ArticlePubMed
- Walczak CE, Heald R: Mechanisms of mitotic spindle assembly and function. Int Rev Cytol 2008, 265: 111–158.View ArticlePubMed
- Zimmerman W, Sparks CA, Doxsey SJ: Amorphous no longer: the centrosome comes into focus. Curr Opin Cell Biol 1999,11(1):122–128. 10.1016/S0955-0674(99)80015-5View ArticlePubMed
- Azimzadeh J, Bornens M: Structure and duplication of the centrosome. J Cell Sci 2007,120(Pt 13):2139–2142.View ArticlePubMed
- Kashina AS, Rogers GC, Scholey JM: The bimC family of kinesins: essential bipolar mitotic motors driving centrosome separation. Biochim Biophys Acta 1997,1357(3):257–271. 10.1016/S0167-4889(97)00037-2View ArticlePubMed
- Kapoor TM, Mayer TU, Coughlin ML, Mitchison TJ: Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5. J Cell Biol 2000,150(5):975–988. 10.1083/jcb.150.5.975View ArticlePubMed CentralPubMed
- Sharp DJ, Yu KR, Sisson JC, Sullivan W, Scholey JM: Antagonistic microtubule-sliding motors position mitotic centrosomes in Drosophila early embryos. Nat Cell Biol 1999,1(1):51–54. 10.1038/9025View ArticlePubMed
- Gascoigne KE, Cheeseman IM: Kinetochore assembly: if you build it, they will come. Curr Opin Cell Biol 2011,23(1):102–108. 10.1016/j.ceb.2010.07.007View ArticlePubMed CentralPubMed
- DeLuca JG, Musacchio A: Structural organization of the kinetochore-microtubule interface. Curr Opin Cell Biol 2012,24(1):48–56. 10.1016/j.ceb.2011.11.003View ArticlePubMed CentralPubMed
- Musacchio A, Salmon ED: The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 2007,8(5):379–393. 10.1038/nrm2163View ArticlePubMed
- Sharp DJ, Rogers GC, Scholey JM: Cytoplasmic dynein is required for poleward chromosome movement during mitosis in Drosophila embryos. Nat Cell Biol 2000,2(12):922–930. 10.1038/35046574View ArticlePubMed
- Kapoor TM, Lampson MA, Hergert P, Cameron L, Cimini D, Salmon ED, McEwen BF, Khodjakov A: Chromosomes can congress to the metaphase plate before biorientation. Science 2006,311(5759):388–391. 10.1126/science.1122142View ArticlePubMed
- Yang Z, Tulu US, Wadsworth P, Rieder CL: Kinetochore dynein is required for chromosome motion and congression independent of the spindle checkpoint. Curr Biol 2007,17(11):973–980. 10.1016/j.cub.2007.04.056View ArticlePubMed CentralPubMed
- Levesque AA, Compton DA: The chromokinesin Kid is necessary for chromosome arm orientation and oscillation, but not congression, on mitotic spindles. J Cell Biol 2001,154(6):1135–1146. 10.1083/jcb.200106093View ArticlePubMed CentralPubMed
- Rieder CL, Alexander SP: Kinetochores are transported poleward along a single astral microtubule during chromosome attachment to the spindle in newt lung cells. J Cell Biol 1990,110(1):81–95. 10.1083/jcb.110.1.81View ArticlePubMed
- Skibbens RV, Skeen VP, Salmon ED: Directional instability of kinetochore motility during chromosome congression and segregation in mitotic newt lung cells: a push-pull mechanism. J Cell Biol 1993,122(4):859–875. 10.1083/jcb.122.4.859View ArticlePubMed
- Stumpff J, Wagenbach M, Franck A, Asbury CL, Wordeman L: Kif18A and Chromokinesins Confine Centromere Movements via Microtubule Growth Suppression and Spatial Control of Kinetochore Tension. Dev Cell 2012,22(5):1017–1029. 10.1016/j.devcel.2012.02.013View ArticlePubMed CentralPubMed
- Rieder CL, Schultz A, Cole R, Sluder G: Anaphase onset in vertebrate somatic cells is controlled by a checkpoint that monitors sister kinetochore attachment to the spindle. J Cell Biol 1994,127(5):1301–1310. 10.1083/jcb.127.5.1301View ArticlePubMed
- Cimini D: Merotelic kinetochore orientation, aneuploidy, and cancer. Biochim Biophys Acta 2008,1786(1):32–40.PubMed
- Nicholson JM, Cimini D: How mitotic errors contribute to karyotypic diversity in cancer. Adv Cancer Res 2011, 112: 43–75.View ArticlePubMed
- Boveri T: Concerning the origin of malignant tumours by Theodor Boveri. Translated and annotated by Henry Harris. J Cell Sci 2008,121(Supplement 1):1–84. 10.1242/jcs.025742View ArticlePubMed
- Boveri T: Zur Frage der Entstehung maligner Tumoren. Jena, Germany: Gustav Fischer Verlag; 1914.
- Heneen WK: Kinetochores and microtubules in multipolar mitosis and chromosome orientation. Exp Cell Res 1975,91(1):57–62. 10.1016/0014-4827(75)90140-8View ArticlePubMed
- Wheatley SP, Wang Y: Midzone microtubule bundles are continuously required for cytokinesis in cultured epithelial cells. J Cell Biol 1996,135(4):981–989. 10.1083/jcb.135.4.981View ArticlePubMed
- Sluder G, Thompson EA, Miller FJ, Hayes J, Rieder CL: The checkpoint control for anaphase onset does not monitor excess numbers of spindle poles or bipolar spindle symmetry. J Cell Sci 1997,110(Pt 4):421–429.PubMed
- Ghadimi BM, Sackett DL, Difilippantonio MJ, Schrock E, Neumann T, Jauho A, Auer G, Ried T: Centrosome amplification and instability occurs exclusively in aneuploid, but not in diploid colorectal cancer cell lines, and correlates with numerical chromosomal aberrations. Genes Chromosomes Cancer 2000,27(2):183–190. 10.1002/(SICI)1098-2264(200002)27:2<183::AID-GCC10>3.0.CO;2-PView ArticlePubMed
- Lingle WL, Barrett SL, Negron VC, D'Assoro AB, Boeneman K, Liu W, Whitehead CM, Reynolds C, Salisbury JL: Centrosome amplification drives chromosomal instability in breast tumor development. Proc Natl Acad Sci U S A 2002,99(4):1978–1983. 10.1073/pnas.032479999View ArticlePubMed CentralPubMed
- Pihan GA, Purohit A, Wallace J, Malhotra R, Liotta L, Doxsey SJ: Centrosome defects can account for cellular and genetic changes that characterize prostate cancer progression. Cancer Res 2001,61(5):2212–2219.PubMed
- Gisselsson D, Jin Y, Lindgren D, Persson J, Gisselsson L, Hanks S, Sehic D, Mengelbier LH, Ora I, Rahman N, et al.: Generation of trisomies in cancer cells by multipolar mitosis and incomplete cytokinesis. Proc Natl Acad Sci U S A 2010,107(47):20489–20493. 10.1073/pnas.1006829107View ArticlePubMed CentralPubMed
- Ganem NJ, Godinho SA, Pellman D: A mechanism linking extra centrosomes to chromosomal instability. Nature 2009,460(7252):278–282. 10.1038/nature08136View ArticlePubMed CentralPubMed
- Sato N, Mizumoto K, Nakamura M, Maehara N, Minamishima YA, Nishio S, Nagai E, Tanaka M: Correlation between centrosome abnormalities and chromosomal instability in human pancreatic cancer cells. Cancer Genet Cytogenet 2001,126(1):13–19. 10.1016/S0165-4608(00)00384-8View ArticlePubMed
- Saunders WS, Shuster M, Huang X, Gharaibeh B, Enyenihi AH, Petersen I, Gollin SM: Chromosomal instability and cytoskeletal defects in oral cancer cells. Proc Natl Acad Sci U S A 2000,97(1):303–308. 10.1073/pnas.97.1.303View ArticlePubMed CentralPubMed
- Jin Y, Stewenius Y, Lindgren D, Frigyesi A, Calcagnile O, Jonson T, Edqvist A, Larsson N, Lundberg LM, Chebil G, et al.: Distinct mitotic segregation errors mediate chromosomal instability in aggressive urothelial cancers. Clin Cancer Res 2007,13(6):1703–1712. 10.1158/1078-0432.CCR-06-2705View ArticlePubMed
- Kaplan KB, Burds AA, Swedlow JR, Bekir SS, Sorger PK, Nathke IS: A role for the Adenomatous Polyposis Coli protein in chromosome segregation. Nat Cell Biol 2001,3(4):429–432. 10.1038/35070123View ArticlePubMed
- Reing JE, Gollin SM, Saunders WS: The occurrence of chromosome segregational defects is an intrinsic and heritable property of oral squamous cell carcinoma cell lines. Cancer Genet Cytogenet 2004,150(1):57–61. 10.1016/j.cancergencyto.2003.08.002View ArticlePubMed
- Stewenius Y, Jin Y, Ora I, de Kraker J, Bras J, Frigyesi A, Alumets J, Sandstedt B, Meeker AK, Gisselsson D: Defective chromosome segregation and telomere dysfunction in aggressive Wilms' tumors. Clin Cancer Res 2007,13(22 Pt 1):6593–6602.View ArticlePubMed
- Silkworth WT, Nardi IK, Scholl LM, Cimini D: Multipolar spindle pole coalescence is a major source of kinetochore mis-attachment and chromosome mis-segregation in cancer cells. PLoS One 2009,4(8):e6564. 10.1371/journal.pone.0006564View ArticlePubMed CentralPubMed
- Kwon M, Godinho SA, Chandhok NS, Ganem NJ, Azioune A, Thery M, Pellman D: Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. Genes Dev 2008,22(16):2189–2203. 10.1101/gad.1700908View ArticlePubMed CentralPubMed
- Quintyne NJ, Reing JE, Hoffelder DR, Gollin SM, Saunders WS: Spindle multipolarity is prevented by centrosomal clustering. Science 2005,307(5706):127–129. 10.1126/science.1104905View ArticlePubMed
- Acilan C, Saunders WS: A tale of too many centrosomes. Cell 2008,134(4):572–575. 10.1016/j.cell.2008.08.007View ArticlePubMed
- Basto R, Brunk K, Vinadogrova T, Peel N, Franz A, Khodjakov A, Raff JW: Centrosome amplification can initiate tumorigenesis in flies. Cell 2008,133(6):1032–1042. 10.1016/j.cell.2008.05.039View ArticlePubMed CentralPubMed
- Logarinho E, Maffini S, Barisic M, Marques A, Toso A, Meraldi P, Maiato H: CLASPs prevent irreversible multipolarity by ensuring spindle-pole resistance to traction forces during chromosome alignment. Nat Cell Biol 2012,14(3):295–303. 10.1038/ncb2423View ArticlePubMed
- Leber B, Maier B, Fuchs F, Chi J, Riffel P, Anderhub S, Wagner L, Ho AD, Salisbury JL, Boutros M, et al.: Proteins required for centrosome clustering in cancer cells. Sci Transl Med 2010,2(33):33ra-38ra.View Article
- Tanenbaum ME, Medema RH: Mechanisms of centrosome separation and bipolar spindle assembly. Dev Cell 2010,19(6):797–806. 10.1016/j.devcel.2010.11.011View ArticlePubMed
- Brito DA, Yang Z, Rieder CL: Microtubules do not promote mitotic slippage when the spindle assembly checkpoint cannot be satisfied. J Cell Biol 2008,182(4):623–629. 10.1083/jcb.200805072View ArticlePubMed CentralPubMed
- Rieder CL, Maiato H: Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint. Dev Cell 2004,7(5):637–651. 10.1016/j.devcel.2004.09.002View ArticlePubMed
- Leizerman I, Avunie-Masala R, Elkabets M, Fich A, Gheber L: Differential effects of monastrol in two human cell lines. Cell Mol Life Sci 2004,61(16):2060–2070.View ArticlePubMed
- Rosenblatt J: Spindle assembly: asters part their separate ways. Nat Cell Biol 2005,7(3):219–222. 10.1038/ncb0305-219View ArticlePubMed
- Rosenblatt J, Cramer LP, Baum B, McGee KM: Myosin II-dependent cortical movement is required for centrosome separation and positioning during mitotic spindle assembly. Cell 2004,117(3):361–372. 10.1016/S0092-8674(04)00341-1View ArticlePubMed
- Toso A, Winter JR, Garrod AJ, Amaro AC, Meraldi P, McAinsh AD: Kinetochore-generated pushing forces separate centrosomes during bipolar spindle assembly. J Cell Biol 2009,184(3):365–372. 10.1083/jcb.200809055View ArticlePubMed CentralPubMed
- McHedlishvili N, Wieser S, Holtackers R, Mouysset J, Belwal M, Amaro AC, Meraldi P: Kinetochores accelerate centrosome separation to ensure faithful chromosome segregation. J Cell Sci 2012,125(Pt 4):906–918.View ArticlePubMed
- Whitehead CM, Winkfein RJ, Rattner JB: The relationship of HsEg5 and the actin cytoskeleton to centrosome separation. Cell Motil Cytoskeleton 1996,35(4):298–308. 10.1002/(SICI)1097-0169(1996)35:4<298::AID-CM3>3.0.CO;2-3View ArticlePubMed
- Rattner JB, Berns MW: Centriole behavior in early mitosis of rat kangaroo cells (PTK2). Chromosoma 1976,54(4):387–395. 10.1007/BF00292817View ArticlePubMed
- Mole Bajer J: The role of centrioles in the development of the astral spindle (newt). Cytobios 1975, 13: 117–140.
- Silkworth WT, Nardi IK, Paul R, Mogilner A, Cimini D: Timing of centrosome separation is important for accurate chromosome segregation. Mol Biol Cell 2012,23(3):401–411. 10.1091/mbc.E11-02-0095View ArticlePubMed CentralPubMed
- Kaseda K, McAinsh A, Cross RA: A countdown clock in mitotic prophase. ASCB Abstracts. vol 2009, 294. http://www.ascb.org/meetings/Abstract/2009_Regular_Abstracts.pdf;2009:615/B562
- Aubin JE, Osborn M, Weber K: Variations in the distribution and migration of centriole duplexes in mitotic PtK2 cells studied by immunofluorescence microscopy. J Cell Sci 1980, 43: 177–194.PubMed
- Paul R, Wollman R, Silkworth WT, Nardi IK, Cimini D, Mogilner A: Computer simulations predict that chromosome movements and rotations accelerate mitotic spindle assembly without compromising accuracy. Proc Natl Acad Sci U S A 2009,106(37):15708–15713. 10.1073/pnas.0908261106View ArticlePubMed CentralPubMed
- Cimini D, Fioravanti D, Salmon ED, Degrassi F: Merotelic kinetochore orientation versus chromosome mono-orientation in the origin of lagging chromosomes in human primary cells. J Cell Sci 2002,115(Pt 3):507–515.PubMed
- Cimini D, Cameron LA, Salmon ED: Anaphase spindle mechanics prevent mis-segregation of merotelically oriented chromosomes. Curr Biol 2004,14(23):2149–2155. 10.1016/j.cub.2004.11.029View ArticlePubMed
- Khodjakov A, Cole RW, McEwen BF, Buttle KF, Rieder CL: Chromosome fragments possessing only one kinetochore can congress to the spindle equator. J Cell Biol 1997,136(2):229–240. 10.1083/jcb.136.2.229View ArticlePubMed CentralPubMed
- Wise DA, Brinkley BR: Mitosis in cells with unreplicated genomes (MUGs): spindle assembly and behavior of centromere fragments. Cell Motil Cytoskeleton 1997,36(3):291–302. 10.1002/(SICI)1097-0169(1997)36:3<291::AID-CM9>3.0.CO;2-AView ArticlePubMed
- Yu HG, Dawe RK: Functional redundancy in the maize meiotic kinetochore. J Cell Biol 2000,151(1):131–142. 10.1083/jcb.151.1.131View ArticlePubMed CentralPubMed
- Cimini D, Wan X, Hirel CB, Salmon ED: Aurora kinase promotes turnover of kinetochore microtubules to reduce chromosome segregation errors. Curr Biol 2006, 16: 1711–1718. 10.1016/j.cub.2006.07.022View ArticlePubMed
- DeLuca JG, Gall WE, Ciferri C, Cimini D, Musacchio A, Salmon ED: Kinetochore microtubule dynamics and attachment stability are regulated by Hec1. Cell 2006,127(5):969–982. 10.1016/j.cell.2006.09.047View ArticlePubMed
- Weaver BA, Cleveland DW: Does aneuploidy cause cancer? Curr Opin Cell Biol 2006,18(6):658–667. 10.1016/j.ceb.2006.10.002View ArticlePubMed
- Lengauer C, Kinzler KW, Vogelstein B: Genetic instability in colorectal cancers. Nature 1997,386(6625):623–627. 10.1038/386623a0View ArticlePubMed
- Rajagopalan H, Lengauer C: CIN-ful cancers. Cancer Chemother Pharmacol 2004,54(Suppl 1):S65-S68.PubMed
- Yuen KW, Desai A: The wages of CIN. J Cell Biol 2008,180(4):661–663. 10.1083/jcb.200801030View ArticlePubMed CentralPubMed
- Thompson SL, Compton DA: Examining the link between chromosomal instability and aneuploidy in human cells. J Cell Biol 2008,180(4):665–672. 10.1083/jcb.200712029View ArticlePubMed CentralPubMed
- Bakhoum SF, Genovese G, Compton DA: Deviant kinetochore microtubule dynamics underlie chromosomal instability. Curr Biol 2009,19(22):1937–1942. 10.1016/j.cub.2009.09.055View ArticlePubMed CentralPubMed
- D'Assoro AB, Lingle WL, Salisbury JL: Centrosome amplification and the development of cancer. Oncogene 2002,21(40):6146–6153. 10.1038/sj.onc.1205772View ArticlePubMed
- Lingle WL, Salisbury JL: Altered centrosome structure is associated with abnormal mitoses in human breast tumors. Am J Pathol 1999,155(6):1941–1951. 10.1016/S0002-9440(10)65513-7View ArticlePubMed CentralPubMed
- Nigg EA: Centrosome aberrations: cause or consequence of cancer progression? Nat Rev Cancer 2002,2(11):815–825. 10.1038/nrc924View ArticlePubMed
- Gisselsson D, Jonson T, Yu C, Martins C, Mandahl N, Wiegant J, Jin Y, Mertens F, Jin C: Centrosomal abnormalities, multipolar mitoses, and chromosomal instability in head and neck tumours with dysfunctional telomeres. Br J Cancer 2002,87(2):202–207.View ArticlePubMed CentralPubMed
- Gisselsson D, Palsson E, Yu C, Mertens F, Mandahl N: Mitotic instability associated with late genomic changes in bone and soft tissue tumours. Cancer Lett 2004,206(1):69–76. 10.1016/j.canlet.2003.10.022View ArticlePubMed
- Hyman AA, White JG: Determination of cell division axes in the early embryogenesis of Caenorhabditis elegans. J Cell Biol 1987,105(5):2123–2135. 10.1083/jcb.105.5.2123View ArticlePubMed
- Cytrynbaum EN, Sommi P, Brust-Mascher I, Scholey JM, Mogilner A: Early spindle assembly in Drosophila embryos: role of a force balance involving cytoskeletal dynamics and nuclear mechanics. Mol Biol Cell 2005,16(10):4967–4981. 10.1091/mbc.E05-02-0154View ArticlePubMed CentralPubMed
- Civelekoglu-Scholey G, Tao L, Brust-Mascher I, Wollman R, Scholey JM: Prometaphase spindle maintenance by an antagonistic motor-dependent force balance made robust by a disassembling lamin-B envelope. J Cell Biol 2010,188(1):49–68. 10.1083/jcb.200908150View ArticlePubMed CentralPubMed
- Kaltschmidt JA, Davidson CM, Brown NH, Brand AH: Rotation and asymmetry of the mitotic spindle direct asymmetric cell division in the developing central nervous system. Nat Cell Biol 2000,2(1):7–12. 10.1038/71323View ArticlePubMed
- Magidson V, O'Connell CB, Loncarek J, Paul R, Mogilner A, Khodjakov A: The Spatial Arrangement of Chromosomes during Prometaphase Facilitates Spindle Assembly. Cell 2011,146(4):555–567. 10.1016/j.cell.2011.07.012View ArticlePubMed CentralPubMed
- Holland AJ, Cleveland DW: Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat Rev Mol Cell Biol 2009,10(7):478–487.View ArticlePubMed CentralPubMed
- Gillies TE, Cabernard C: Cell division orientation in animals. Curr Biol 2011,21(15):R599-R609. 10.1016/j.cub.2011.06.055View ArticlePubMed
- Morin X, Bellaiche Y: Mitotic spindle orientation in asymmetric and symmetric cell divisions during animal development. Dev Cell 2011,21(1):102–119. 10.1016/j.devcel.2011.06.012View ArticlePubMed
- Toyoshima F, Nishida E: Spindle orientation in animal cell mitosis: roles of integrin in the control of spindle axis. J Cell Physiol 2007,213(2):407–411. 10.1002/jcp.21227View ArticlePubMed
- Robinson JT, Wojcik EJ, Sanders MA, McGrail M, Hays TS: Cytoplasmic dynein is required for the nuclear attachment and migration of centrosomes during mitosis in Drosophila. J Cell Biol 1999,146(3):597–608. 10.1083/jcb.146.3.597View ArticlePubMed CentralPubMed
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.