Kinetochore function: Molecular motors, switches and gates

Current Opinion in Cell Biology

Volumn 8, Issue 3, 1996, Pages 381-388

  Yen, Tim J ^a   Schaar, Bruce T ^b  

^a FOX CHASE CANCER CENTER   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DYNEIN ADENOSINE TRIPHOSPHATASE; KINESIN;

CENTROMERE; CHROMOSOME SEGREGATION; MICROTUBULE; MITOSIS SPINDLE; PRIORITY JOURNAL; REVIEW;

VERTEBRATA;

EID: 0029890528     PISSN: 09550674     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0955-0674(96)80014-7     Document Type: Article

References (47)

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19. Echeverri CJ, Paschal BM, Vaughan KT, Vallee RB: Molecular characterization of 50 kD subunit of dynactin reveals function for the complex in chromosome alignment and spindle organization during mitosis. J Cell Biol 1996, 132:617-633. The discovery that multiple subunits of the dynein-associated complex, dynactin, are detectable at kinetochores further strengthens the support for a role of dynein at kinetochores. Overexpression of the p50 subunit disrupted dynactin complex formation and blocked cells in mitosis; these cells displayed aberrant spindles and unaligned chromosomes. Because the staining of dynein and dynactin at the kinetochores of these blocked cells was diminished compared with wild-type cells, it is suggested that the failure to align chromosomes might be due to a defective kinetochore.
20. Yen TJ, Li G, Schaar BT, Szilak I, Cleveland DW: CENP-E is a putative kinetochore motor that accumulates just before mitosis. Nature 1992, 359:536-539.
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22. Liao M, Li G, Yen TJ: Mitotic regulation of microtubule-crosslinking activity of CENP-E kinetochore protein. Science 1994, 265:394-398. In vitro mapping studies identified microtubule binding by the amino-terminal motor domain of CENP-E in addition to by a second domain at the carboxyl terminus. The carboxy-terminal microtubule-binding domain does not behave as a conventional microtubule-associated protein or motor protein, and its activity is inhibited by phosphorylation induced by cyclin B-cdc2 in vitro and in vivo. The separation of these two microtubule-binding domains by a long extended rod domain may be important for different interactions of the kinetochore with the microtubule.
23. Thrower DA, Jordan MA, Schaar BT, Yen TJ, Wilson L: Mitotic HeLa cells contain a CENP-E-associated minus end-directed microtubule motor. EMBO J 1995, 14:918-926. Describes the biochemical enrichment of a novel microtubule motor activity that is minus-end directed, and which cofractionates with CENP-E (as detected by immunoreactivity). This motor activity was also inhibited by anti-CENP-E antibodies, suggesting that CENP-E may be the first krp that has an amino-terminal motor domain and which exhibits minus end directed motor activity.
24. Lombillo VA, Nislow C, Yen TJ, Gelfand VI, McIntosh JR: Antibodies to the kinesin motor domain and CENP-E inhibit microtubule depolymerization-dependent motion of chromosomes In vitro. J Cell Biol 1995, 128:107-117. The results of this study extended earlier work which showed that chromosomes are capable of coupling chromosome movement to microtubule depolymerization. By testing various antibodies to motor proteins of the kinetochore, the authors of this study were able to identify candidate motors at kinetochores that could provide this coupling activity. The ability of some of these antibodies to inhibit depolymerization-dependent movement also strengthens the assumption that the microtubules were interacting with the kinetochores of the purified chromosomes.
25. Desai A, Mitchison TJ: A new role for motor proteins as couplers to shrinking microtubules. J Cell Biol 1995, 128:1-4.
26. Lombillo VA, Stewart RJ, McIntosh JR: Minus-end directed motion of kinesin-coated microspheres driven by microtubule depolymerization. Nature 1995, 373:161-164. This study reveals for the first time that microtubule motors use a mechanochemical cycle which does not require exogenous ATP and which is able to harness energy from microtubule depolymerization. The ability of a motor to remain attached to a shrinking microtubule provides biochemical models for poleward chromosome movement during congression and anaphase.
27. Wolczak CE, Mitchison TJ, Desai A: XKCM1: a Xenopus kinesin-related protein that regulates microtubule dynamics during mitotic spindle assembly. Cell 1996, 84:37-48. XKCM1 is the first kinesin to be shown to behave as a catastrophe factor. Immunodepletion of XKCM1 from mitotic egg extracts produces giant microtubule asters which contain microtubules that are 10 times longer than normal. This increase results from the suppression of catastrophe in the absence of only XKCM1 (as no other detectable proteins are co-immunoprecipitated). As a member of the KIF2 plus end directed krp superfamily, XKCM1 is predicted to move along the microtubule lattice to the plus end of growing microtubules to induce catastrophe. Like its relative MCAK, the presence of XKCM1 at kinetochores suggests that it could regulate microtubule dynamics and participate in the movement of chromosomes away from the poles.
28. Cassimeris L, Rieder CL, Salmon ED: Microtubule assembly and kinetochore directional instability In vertebrate monopolar spindles: implications for the mechanism of chromosome congression. J Cell Sci 1994, 107:285-287. The results of these studies support the notion that tension exerted at kinetochores is related to the application of a polar-ejection force along the entire chromosome. The kinetochore-to-pole distance was found to correlate with microtubule density within the spindle, but not with kinetochore microtubule number. The oscillatory behaviour of chromosomes is thought to occur because chromosomes persist in poleward movement until resistance supplied by the increasing microtubule density is sufficient to switch to away-from-pole movement.
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33. •]).
34. Jordan MA, Toso RJ, Thrower D, Wilson L: Mechanism of mitotic block and inhibition of cell proliferation by taxol at low concentrations. Proc Natl Acad Sci USA 1993, 90:9552-9556.
35. Wendell KL, Wilson K, Jordan MA: Mitotic block in HeLa cells by vinblastine: ultrastructural changes in kinetochore-microtubule attachment and in centrosomes. J Cell Sci 1993, 104:261-274.
36. •] that the checkpoint monitors kinetochore tension.
37. Xiaotong L, Nicklas RB: Mitotic forces control a cell-cycle checkpoint. Nature 1995, 373:630-632. A classic experiment which takes advantage of the fact that one of the X chromosomes of the trivalent sex chromosomes in mantis spermatocytes fails to pair with the single Y chromosome and blocks entry into anaphase. By pulling on the unattached kinetochore of the unpaired X chromosome, the block is relieved and chromosome segregation proceeds. Thus, tension is directly monitored by the checkpoint in mantis spermatocytes.
38. McIntosh JR: Structural and mechanical control of mitotic progression. Cold Spring Harb Symp Quant Biol 1991, 56:613-619.
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40. Gorbsky GJ, Ricketts WA: Differential expression of a phosphoepitope at the kinetochores of moving chromosomes. J Cell Biol 1993, 122:1311-1321.
41. Campbell MS, Gorbsky GJ: Microinjection of mitotic cells with the 3F3/2 anti-phosphoepitope antibody delays the onset of anaphase. J Cell Biol 1995, 129:1195-1204. The role of the 3F3/2-labeled phospho-epitope in mitosis was tested by microinjection of the 3F3/2 monoclonal antibody. As in vitro thiophosphorylation of kinetochore proteins was found to switch the kinetochore motor activity from minus-end to plus-end directed (see [9]), and because the 3F3/2-stained phospho-epitope was differentially expressed on congressing kinetochores, one prediction was that this epitope elicited in vivo switching of kinetochore motors. As cells injected with anti-phospho-epitope were able to align their chromosomes at the metaphase plate, switching by the phosphorylation of the phospho-epitope was probably unlikely. However, because the blocked cells exhibited strong 3F3/2 staining at their kinetochores, the other possibility is that this phospho-epitope was recognized by the spindle-assembly checkpoint. Indeed, when injected cells eventually entered anaphase, 3F3/2 staining at the kinetochore was lost.
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45. Nicklas RB, Ward SC, Gorbsky GJ: Kinetochore chemistry is sensitive to tension and may link mitotic forces to a cell cycle checkpoint. J Cell Biol 1995, 130:929-939. Using the 3F3/2 monoclonal antibody, it was discovered that the amount of tension that was exerted at the kinetochores of grasshopper spermatocytes correlated directly with the intensity of 3F3/2 staining. Detachment of aligned chromosomes led to an increase in staining intensity. Conversely, tension from normal mitotic forces or resulting from manipulation reduced staining levels. As the spindle-assembly checkpoint is sensitive to kinetochore tension in grasshopper spermatocytes, the 3F3/2-labeled phospho-epitope responds to tension and is probably the biochemical signal that is recognized by the checkpoint.
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