Re-evaluating centrosome function

Key Points

  • In most vertebrate cells, centrosomes consist mainly of two substructures — centrioles and pericentriolar material. The pericentriolar material, a meshwork of fibres and protein aggregates, seems to be the site of microtubule nucleation. The exact function of centrioles is unclear, but they may mediate the recruitment and organization of centrosome components.

  • Centrosomes are the main site of microtubule nucleation in most cells. Different types of molecules are thought to mediate microtubule nucleation, anchoring and finally, release.

  • Many centrosome proteins undergo cell-cycle-regulated assembly onto centrosomes. Both dynein-dependent and -independent pathways may act redundantly to mediate centrosome assembly, with different pathways dominanting in different cell types or at different times during the cell cycle or development.

  • Although it now appears that centrosomes are not strictly required for bipolar spindle assembly, centrosome-mediated assembly is likely to be an important redundant pathway that ensures high fidelty of chromosome segregation.

  • New roles for centrosomes are now emerging. These include positioning the mitotic spindle, the completion of cytokinesis, G1 to S progression, and initiation DNA replication. Centrosomes might also have a role in coordinating actin poymerization during pseudocleavage in Drosophila — a role that seems to be independent of microtubules and suggests that centrosomes might act as diffusion centres for signalling molecules.

  • Centrosome duplication occurs once per cell cycle, and is tightly coordinated with events such as cell-cycle progression and DNA replication. The molecular pathway that controls duplication is now being revealed, and includes both cell-cycle regulators and downstream factors such as nucleophosmin, the degradation of which may be required for centriole splitting.

  • Centrosomes act as anchoring sites for regulators of diverse cellular functions. The significance of this association and how these factors communicate with the rest of the cell is an area of great interest.

  • Because both centrosomes and acentriolar microtubule-organizing centres organize dysfunctional mitotic spindles, both have the potential to contribute to genetic instability during tumorigenesis. However, a driect link between centrosomes and cancer has not yet been established.

Abstract

Over the past 100 years, the centrosome has risen in status from an enigmatic organelle, located at the focus of microtubules, to a key player in cell-cycle progression and cellular control. A growing body of evidence indicates that centrosomes might not be essential for spindle assembly, whereas recent data indicate that they might be important for initiating S phase and completing cytokinesis. Molecules that regulate centrosome duplication have been identified, and the expanding list of intriguing centrosome-anchored activities, the functions of which have yet to be determined, promises continued discovery.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Centrosome structure.
Figure 2: Model for microtubule nucleation, release and anchoring at centrosomes and in epithelial cells.
Figure 3: Models for centrosome protein assembly.
Figure 4: Centrosome and spindle pole body positioning during cytokinesis.
Figure 5: Centrosome duplication.
Figure 6: Intrinsic activities and external influences of centrosomes.
Figure 7: Two pathways for generating centrosome defects that could lead to genetic instability and loss of cell polarity in cancer.
Figure 8: Abnormal centrosomes in a human tumour and in a human tumour cell line.

References

  1. 1

    Wheatley, D. N. The Centriole (Elsevier Biomedical Press, Amsterdam, 1982).

    Google Scholar 

  2. 2

    Francis, S. E. & Davis, T. N. The spindle pole body of Saccharomyces cerevisiae: architecture and assembly of the core components. Curr. Top. Dev. Biol. 49, 105–132 (2000).

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Schiebel, E. γ-tubulin complexes: binding to the centrosome, regulation and microtubule nucleation. Curr. Opin. Cell Biol. 12, 113–118 (2000).

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Wigge, P. et al. Analysis of the Saccharomyces spindle pole by matrix-assisted laser desorbtion/ionization (MALDI) mass spectrometry. J. Cell Biol. 141, 967–977 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5

    Gould, R. R. & Borisy, G. G. The pericentriolar material in Chinese hamster ovary cells nucleates microtubule formation. J. Cell Biol. 73, 601–615 (1977).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6

    Dictenberg, J. et al. Pericentrin and γ-tubulin form a protein complex and are organized into a novel lattice at the centrosome. J. Cell Biol. 141, 163–174 (1998).Identifies pericentrin as a protein that interacts with the γ-tubulin ring complex and co-localizes with γ-tubulin at the centrosome (also see reference 34).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7

    Vogel, J. M., Stearns, T., Rieder, C. L. & Palazzo, R. E. Centrosomes isolated from Spistula solidissima oocytes contain rings and an unusual stoichiometric ratio of α/β-tubulin. J. Cell Biol. 137, 193–202 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8

    Moritz, M., Braunfeld, M. B., Sedat, J. W., Alberts, B. & Agard, D. A. Microtubule nucleation by γ-tubulin-containing rings in the centrosome. Nature 378, 638–640 (1995).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Wheatley, D. N., Wang, A. M. & Strugnell, G. E. Expression of primary cilia in mammalian cells. Cell Biol. Int. 20, 73–81 (1996).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Pazour, G. J. et al. Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J. Cell Biol. 151, 709–718 (2000).Demonstration that a centriole protein required for formation of cilia and flagella is involved in polycystic kidney disease.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Hewitson, L., Simerly, C. & Schatten, G. Cytoskeletal aspects of assisted fertilization. Semin. Reprod. Med. 18, 151–159 (2000).

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Manandhar, G., Simerly, C. & Schatten, G. Highly degenerated distal centrioles in rhesus and human spermatozoa. Hum. Reprod. 15, 256–263 (2000).

    CAS  PubMed  Article  Google Scholar 

  13. 13

    Bobinnec, Y. et al. Centriole disassembly in vivo and its effect on centrosome structure and function in vertebrate cells. J. Cell Biol. 143, 1575–1589 (1998).Shows that disruption of centrioles causes dispersion of PCM components, indicating a role for centrioles in centrosome organization.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14

    Evans, L., Mitchison, T. & Kirschner, M. Influence of the centrosome on the structure of nucleated microtubules. J. Cell Biol. 100, 1185–1191 (1985).

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Oakley, B. R., Oakley, C. E., Yoon, Y. & Jung, M. K. γ-tubulin is a component of the spindle pole body that is essential for microtubule function in Aspergillus nidulans. Nature 338, 662–664 (1990).

    Article  Google Scholar 

  16. 16

    Zheng, Y., Wong, M. L., Alberts, B. & Mitchison, T. Nucleation of microtubule assembly by a γ-tubulin-containing ring complex. Nature 378, 578–583 (1995).

    CAS  PubMed  Article  Google Scholar 

  17. 17

    Stearns, T. & Kirschner, M. Reconstitution of centrosome assembly, role of γ-tubulin. Cell 76, 623–637 (1994).

    CAS  PubMed  Article  Google Scholar 

  18. 18

    Wiese, C. & Zheng, Y. A new function for the γ-tubulin ring complex as a microtubule minus-end cap. Nature Cell Biol. 2, 358–364 (2000).

    CAS  PubMed  Article  Google Scholar 

  19. 19

    Zimmerman, W., Sparks, C. A. & Doxsey, S. J. Amorphous no longer: the centrosome comes into focus. Curr. Opin. Cell Biol. 11, 122–128 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20

    Zimmerman, W. & Doxsey, S. J. Construction of centrosomes and spindle poles by molecular motor-driven assembly of protein particles. Traffic 1, 927–934 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Moritz, M., Zheng, Y., Alberts, B. M. & Oegema, K. Recruitment of the γ-tubulin ring complex to Drosophila salt-stripped centrosome scaffolds. J. Cell Biol. 142, 775–786 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22

    Oegema, K. et al. Characterization of two related Drosophila γ-tubulin complexes that differ in their ability to nucleate microtubules. J. Cell Biol. 144, 721–733 (1999).Identification of two γ-tubulin complexes of different sizes in Drosophila embryos.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Leguy, R., Melki, R., Pantaloni, D. & Carlier, M. F. Monomeric γ-tubulin nucleates microtubules. J. Biol. Chem. 275, 21975–21980 (2000).

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Murphy, S. M., Urbani, L. & Stearns, T. The mammalian γ-tubulin complex contains homologues of the yeast spindle pole body components spc97p and spc98p. J. Cell Biol. 141, 663–674 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25

    Gunawardane, R. N., Lizarraga, S. B., Wiese, C., Wilde, A. & Zheng, Y. γ-tubulin complexes and their role in microtubule nucleation. Curr. Top. Dev. Biol. 49, 55–73 (2000).

    CAS  PubMed  Article  Google Scholar 

  26. 26

    Keating, T. J. & Borisy, G. G. Immunostructural evidence for the template mechanism of microtubule nucleation. Nature Cell Biol. 2, 352–357 (2000).

    CAS  PubMed  Article  Google Scholar 

  27. 27

    Moritz, M., Braunfeld, M. B., Guenebaut, V., Heuser, J. & Agard, D. A. Structure of the γ-tubulin ring complex: a template for microtubule nucleation. Nature Cell Biol. 2, 365–370 (2000).

    CAS  PubMed  Article  Google Scholar 

  28. 28

    Erickson, H. P. & Stoffler, D. Protofilaments and rings, two conformations of the tubulin family conserved from bacterial FtsZ to α/β- and γ-tubulin. J. Cell Biol. 135, 5–8 (1996).

    CAS  Article  PubMed  Google Scholar 

  29. 29

    Erickson, H. P. γ-tubulin nucleation: template or protofilament? Nature Cell Biol. 2, E93–E96 (2000).

    CAS  PubMed  Article  Google Scholar 

  30. 30

    Knop, M. & Schiebel, E. Spc98p and Spc97p of the yeast γ-tubulin complex mediate binding to the spindle pole body via their interaction with Spc110p. EMBO J. 16, 6985–6995 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31

    Knop, M. & Schiebel, E. Receptors determine the cellular localization of a γ-tubulin complex and thereby the site of microtubule formation. EMBO J. 17, 3952–3967 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32

    do Carmo Avides, M. & Glover, D. M. Abnormal spindle protein, ASP, and the integrity of mitotic centrosomal microtubule organizing centers. Science 283, 1733–1735 (1999).

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Tassin, A. M., Celati, C., Paintrand, M. & Bornens, M. Identification of an Spc110p-related protein in vertebrates. J. Cell Sci. 110, 2533–2545 (1997).

    CAS  PubMed  Google Scholar 

  34. 34

    Flory, M. R., Moser, M. J., Monnat, R. J. Jr & Davis, T. N. Identification of a human centrosomal calmodulin-binding protein that shares homology with pericentrin. Proc. Natl Acad. Sci. USA 97, 5919–5923 (2000).Shows that an apparent isoform of human pericentrin, pericentrinB/kendrin has a calmodulin-binding domain that is homologous to the yeast protein Spc110, which binds γ-tubulin complexes at the spindle pole body (also see reference 6).

    CAS  PubMed  Article  Google Scholar 

  35. 35

    Li, Q. et al. Kendrin/pericentrin-B, a centrosome protein with homology to pericentrin that complexes with PCM-1. J. Cell Sci. 114, 797–809 (2001).

    CAS  PubMed  Google Scholar 

  36. 36

    Doxsey, S. J., Stein, P., Evans, L., Calarco, P. & Kirschner, M. Pericentrin, a highly conserved protein of centrosomes involved in microtubule orgainzation. Cell 76, 639–650 (1994).

    CAS  PubMed  Article  Google Scholar 

  37. 37

    Nigg, E. A. Cell division mitotic kinases as regulators of cell division and its checkpoints. Nature Rev. Mol. Cell Biol. 2, 21–32 (2001).

    CAS  Article  Google Scholar 

  38. 38

    Donaldson, M. M., Tavares, A. A., Ohkura, H., Deak, P. & Glover, D. M. Metaphase arrest with centromere separation in polo mutants of Drosophila. J. Cell Biol. 153, 663–676 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Do Carmo Avides, M., Tavares, A. & Glover, D. M. Polo kinase and Asp are needed to promote the mitotic organizing activity of centrosomes. Nature Cell Biol. 3, 421–424 (2001).Shows that Polo kinase and Asp are in the same complex, that Polo phosphorylates Asp in vitro and that both active Polo and phosphorylation of Asp are required for recruitment of γ-tubulin complexes to centrosomes.

    CAS  PubMed  Article  Google Scholar 

  40. 40

    Feng, Y. et al. Association of polo-like kinase with β-and γ-tubulins in a stable complex. Biochem. J. 339, 435–442 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41

    Mogensen, M. M., Mackie, J. B., Doxsey, S. J., Stearns, T. & Tucker, J. B. Centrosomal deployment of γ-tubulin and pericentrin: evidence for a microtubule-nucleating domain and a minus-end docking domain in certain mouse epithelial cells. Cell Motil. Cytoskel. 36, 276–290 (1997).Demonstration that unique microtubule minus-end anchoring sites exist in epithelial cells that lack proteins involved in microtubule nucleation.

    CAS  Article  Google Scholar 

  42. 42

    Mogensen, M. M., Malik, A., Piel, M., Bouckson-Castaing, V. & Bornens, M. Microtubule minus-end anchorage at centrosomal and non-centrosomal sites: the role of ninein. J. Cell Sci. 113, 3013–3023 (2000).Identification of a protein ninein that localizes to unique microtubule minus-end anchoring sites in epithelial cells and to specializations on the maternal centriole involved in microtubule anchoring (also see reference 41).

    CAS  PubMed  Google Scholar 

  43. 43

    Gromley, A. et al. A novel centriolar protein with a centrosomal function. Mol. Biol. Cell 11, 90 (2000).

  44. 44

    Mogensen, M. M. Microtubule release and capture in epithelial cells. Biol. Cell 91, 331–341 (1999).

    CAS  PubMed  Article  Google Scholar 

  45. 45

    Chretien, D., Buendia, B., Fuller, S. D. & Karsenti, E. Reconstruction of the centrosome cycle from electron micrographs. J. Struct. Biol. 120, 117–133 (1997).

    CAS  PubMed  Article  Google Scholar 

  46. 46

    Mitchison, T. & Salmon, E. D. Poleward kinetochore movement occurs during both metaphase and anaphase-A in newt lung cells mitosis. J. Cell Biol. 119, 569–582 (1992).

    CAS  PubMed  Article  Google Scholar 

  47. 47

    Keating, T. J., Peloquin, J. G., Rodionove, V., Momcilovic, D. & Borisy, G. G. Microtubule release from the centrosome. Proc. Natl Acad. Sci. USA 94, 5078–5083 (1997).Visualization of microtubule release from centrosomes by time-lapse microscopy.

    CAS  PubMed  Article  Google Scholar 

  48. 48

    Hartman, J. et al. Katanin, a microtubule-severing protein, is a novel AA ATPase that targets to the centrosome using a WD40-containing subunit. Cell 93, 277–287 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49

    Ahmad, F. J., Yu, W., McNally, F. J. & Baas, P. W. An essential role for katanin in severing microtubules in the neuron. J. Cell Biol. 145, 305–315 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50

    Desai, A., Verma, S., Mitchison, T. J. & Walczak, C. E. Kin I kinesins are microtubule-destabilizing enzymes. Cell 96, 69–78 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51

    Purohit, A., Tynan, S. H., Vallee, R. & Doxsey, S. J. Direct interaction of pericentrin with cytoplasmic dynein light intermediate chain contributes to mitotic spindle organization. J. Cell Biol. 147, 481–491 (1999).Demonstration that pericentrin interacts directly with a component of cytoplasmic dynein, the light intermediate chain (LIC), suggesting a role for LIC in centrosome assembly.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52

    Tynan, S. H., Purohit, A., Doxsey, S. J. & Vallee, R. B. Light intermediate chain 1 defines a functional subfraction of cytoplasmic dynein which binds to pericentrin. J. Biol. Chem. 275, 32763–32768 (2000).

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Merdes, A., Ramyar, K., Vechio, J. D. & Cleveland, D. W. A complex of NuMA and cytoplasmic dynein is essential for mitotic spindle assembly. Cell 87, 447–458 (1996).

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Balczon, R., Varden, C. E. & Schroer, T. A. Role for microtubules in centrosome doubling in Chinese hamster ovary cells. Cell Motil. Cytoskel. 42, 60–72 (1999).

    CAS  Article  Google Scholar 

  55. 55

    Young, A., Dictenberg, J., Purohit, A., Tuft, R. & Doxsey, S. Dynein-mediated assembly of pericentrin and γ-tubulin onto centrosomes. Mol. Biol. Cell 11, 2047–2056 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Merdes, A., Heald, R., Samejima, K., Earnshaw, W. C. & Cleveland, D. W. Formation of spindle poles by dynein/dynactin-dependent transport of NuMA. J. Cell Biol. 149, 851–862 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57

    Kubo, A., Sasaki, H., Yuba-Kubo, A., Tsukita, S. & Shiina, N. Centriolar satellites: molecular characterization, ATP-dependent movement toward centrioles and possible involvement in ciliogenesis. J. Cell Biol. 147, 969–980 (1999).Shows cytoplasmic dynein-dependent recruitment of pericentrin and PCM-1, to centrosomes, as well as time-lapse imaging of these movements.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58

    Felix, M.-A., Antony, C., Wright, M. & Maro, B. Centrosome assembly in vitro: role of γ-tubulin recriutment in Xenopus sperm aster formation. J. Cell Biol. 124, 19–31 (1994).

    CAS  PubMed  Article  Google Scholar 

  59. 59

    Schnackenberg, B. J., Khodjakov, A., Rieder, C. L. & Palazzo, R. E. The disassembly and reassembly of functional centrosomes in vitro. Proc. Natl Acad. Sci. USA 95, 9295–9300 (1998).

    CAS  PubMed  Article  Google Scholar 

  60. 60

    Khodjakov, A. & Rieder, C. L. The sudden recruitment of γ-tubulin to the centrosome at the onset of mitosis and its dynamic exchange throughout the cell cycle, do not require microtubules. J. Cell Biol. 146, 585–596 (1999).Shows microtubule-independent recruitment of γ-tubulin to centrosomes.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61

    Piel, M., Nordberg, J., Euteneuer, U. & Bornens, M. Centrosome-dependent exit of cytokinesis in animal cells. Science 291, 1550–1553 (2001).Suggests a novel requirement for centrioles in the completion of cytokinesis.

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Piel, M., Meyer, P., Khodjakov, A., Rieder, C. L. & Bornens, M. The respective contributions of the mother and daughter centrioles to centrosome activity and behavior in vertebrate cells. J. Cell Biol. 149, 317–330 (2000).Shows that maternal and daughter centrioles are dynamic structures that nucleate microtubules, but only the maternal centriole retains, and presumably anchors them.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63

    Hyman, A. & Karsenti, E. The role of nucleation in patterning microtubule networks. J. Cell Sci. 111, 2077–2083 (1998).

    CAS  PubMed  Google Scholar 

  64. 64

    Compton, D. A. Spindle assembly in animal cells. Annu. Rev. Biochem. 69, 95–114 (2000).

    CAS  PubMed  Article  Google Scholar 

  65. 65

    Megraw, T. L., Kao, L. R. & Kaufman, T. C. Zygotic development without functional mitotic centrosomes. Curr. Biol. 11, 116–120 (2001).Suggests that centrosomes and astral microtubules are not required for Drosophila development.

    CAS  PubMed  Article  Google Scholar 

  66. 66

    Hinchcliffe, E. H., Miller, F. J., Cham, M., Khodjakov, A. & Sluder, G. Requirement of a centrosomal activity for cell cycle progression through G1 into S phase. Science 291, 1547–1550 (2001).Shows that surgical removal of centrosomes does not affect spindle assembly but inhibits progression from G1 to S phase.

    CAS  PubMed  Article  Google Scholar 

  67. 67

    Khodjakov, A., Cole, R. W., Oakley, B. R. & Rieder, C. L. Centrosome-independent mitotic spindle formation in vertebrates. Curr. Biol. 10, 59–67 (2000).Shows that laser ablation of centrosomes in vertebrate cells does not prevent spindle assembly.

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Heald, R., Regis, T., Habermann, A., Karsenti, E. & Hyman, A. Spindle assembly in Xenopus egg extracts: respective roles of centrosomes and microtubule self-organization. J. Cell Biol. 138, 615–628 (1997).Shows that centrosomes act dominantly in spindle assembly.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    Segal, M. & Bloom, K. Control of spindle polarity and orientation in Saccharomyces cerevisiae. Trends Cell Biol. 11, 160–166 (2001).

    CAS  PubMed  Article  Google Scholar 

  70. 70

    Doe, C. Q. & Bowerman, B. Asymmetric cell division: fly neuroblast meets worm zygote. Curr. Opin. Cell Biol. 13, 68–75 (2001).

    CAS  Article  PubMed  Google Scholar 

  71. 71

    Schuyler, S. C. & Pellman, D. Search, capture and signal: games microtubules and centrosomes play. J. Cell Sci. 114, 247–255 (2001).

    CAS  PubMed  Google Scholar 

  72. 72

    Schuyler, S. C. & Pellman, D. Microtubule 'plus-end-tracking proteins': the end is just the beginning. Cell 105, 421–424 (2001).

    CAS  PubMed  Article  Google Scholar 

  73. 73

    O'Connell, C. B. & Wang, Y. L. Mammalian spindle orientation and position respond to changes in cell shape in a dynein-dependent fashion. Mol. Biol. Cell 11, 1765–1774 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74

    Grill, S. W., Gönczy, P., Stelzer, E. H. & Hyman, A. A. Polarity controls forces governing asymmetric spindle positioning in the Caenorhabditis elegans embryo. Nature 409, 630–633 (2001).

    CAS  Article  PubMed  Google Scholar 

  75. 75

    Khodjakov, A. & Rieder, C. L. Centrosomes enhance the fidelity of cytokinesis in vertebrates and are required for cell cycle progression. J. Cell Biol. 153, 237–242 (2001).Shows that laser ablation of centrosomes causes defects in cytokinesis and blocks cell cycle progression from G1 to S phase.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76

    Cottingham, F. R. & Hoyt, M. A. Mitotic spindle positioning in Saccharomyces cerevisiae is accomplished by antagonistically acting microtubule motor proteins. J. Cell Biol. 138, 1041–1053 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77

    Gachet, Y., Tournier, S., Millar, J. B. & Hyams, J. S. A MAP kinase-dependent actin checkpoint ensures proper spindle orientation in fission yeast. Nature 412, 352–355 (2001).

    CAS  PubMed  Article  Google Scholar 

  78. 78

    Yin, H., Pruyne, D., Huffaker, T. C. & Bretscher, A. Myosin V orientates the mitotic spindle in yeast. Nature 406, 1013–1015 (2000).

    CAS  PubMed  Article  Google Scholar 

  79. 79

    Giansanti, M. G., Gatti, M. & Bonaccorsi, S. The role of centrosomes and astral microtubules during asymmetric division of Drosophila neuroblasts. Development 128, 1137–1145 (2001).

    CAS  PubMed  Google Scholar 

  80. 80

    Roegiers, F., Younger-Shepherd, S., Jan, L. Y. & Jan, Y. N. Two types of asymmetric divisions in the Drosophila sensory organ precursor cell lineage. Nature Cell Biol. 3, 58–67 (2001).

    CAS  Article  PubMed  Google Scholar 

  81. 81

    Rappaport, R. Establishment of the mechanism of cytokinesis in animal cells. Int. Rev. Cytol. 105, 245–281 (1986).

    CAS  PubMed  Article  Google Scholar 

  82. 82

    Adames, N. R. & Cooper, J. A. Microtubule interactions with the cell cortex causing nuclear movements in Saccharomyces cerevisiae. J. Cell Biol. 149, 863–874 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83

    Bardin, A. J., Visintin, R. & Amon, A. A mechanism for coupling exit from mitosis to partitioning of the nucleus. Cell 102, 21–31 (2000).

    CAS  PubMed  Article  Google Scholar 

  84. 84

    Bloecher, A., Venturi, G. M. & Tatchell, K. Anaphase spindle position is monitored by the BUB2 checkpoint. Nature Cell Biol. 2, 556–558 (2000).

    CAS  PubMed  Article  Google Scholar 

  85. 85

    Gruneberg, U., Campbell, K., Simpson, C., Grindlay, J. & Schiebel, E. Nud1p links astral microtubule organization and the control of exit from mitosis. EMBO J. 19, 6475–6488 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86

    Pereira, G., Hofken, T., Grindlay, J., Manson, C. & Schiebel, E. The Bub2p spindle checkpoint links nuclear migration with mitotic exit. Mol. Cell 6, 1–10 (2000).References 83 to 86 describe the identification and characterization of a novel checkpoint that monitors movement of the yeast spindle pole body into the bud at the end of mitosis.

    CAS  PubMed  Article  Google Scholar 

  87. 87

    Doxsey, S. J. Centrosomes as command centres for cellular control. Nature Cell Biol. 3, E105–E108 (2001).

    CAS  PubMed  Article  Google Scholar 

  88. 88

    Pereira, G. & Schiebel, E. The role of the yeast spindle pole body and the mammalian centrosome in regulating late mitotic events. Curr. Opin. Cell Biol. (in the press).

  89. 89

    Andreassen, P. R., Lohez, O. D., Lacroix, F. B. & Margolis, R. L. Tetraploid state induces p53-dependent arrest of nontransformed mammalian cells in G1. Mol. Biol. Cell 12, 1315–1328 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90

    Liu, J., Wang, H. & Balasubramanian, M. K. A checkpoint that monitors cytokinesis in Schizosaccharomyces pombe. J. Cell Sci. 113, 1223–1230 (2000).

    CAS  PubMed  Google Scholar 

  91. 91

    McCollum, D. & Gould, K. L. Timing is everything: regulation of mitotic exit and cytokinesis by the MEN and SIN. Trends Cell Biol. 11, 89–95 (2001).

    CAS  Article  PubMed  Google Scholar 

  92. 92

    Hinchcliffe, E. H., Li, C., Thompson, E. A., Maller, J. L. & Sluder, G. Requirement of Cdk2–cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts. Science 283, 851–854 (1999).

    CAS  PubMed  Article  Google Scholar 

  93. 93

    Lacey, K. R., Jackson, P. K. & Stearns, T. Cyclin-dependent kinase control of centrosome duplication. Proc. Natl Acad. Sci. USA 96, 2817–2822 (1999).References 92 and 93 report the identification of Cdk2–cyclinE/A as regulators of centrosome duplication in Xenopus embryos and extracts.

    CAS  PubMed  Article  Google Scholar 

  94. 94

    Stevenson, V. A., Kramer, J., Kuhn, J. & Theurkauf, W. E. Centrosomes and the Scrambled protein coordinate microtubule-independent actin reorganization. Nature Cell Biol. 3, 68–75 (2001).Microtubule-independent centrosome control of actin deposition in Drosophila embryos.

    CAS  PubMed  Article  Google Scholar 

  95. 95

    Scott, M. P. & O'Farrell, P. H. Spatial programming of gene expression in early Drosophila embryogenesis. Annu. Rev. Cell Biol. 2, 49–80 (1986).

    CAS  PubMed  Article  Google Scholar 

  96. 96

    Sibon, O. C., Kelkar, A., Lemstra, W. & Theurkauf, W. E. DNA-replication/DNA-damage-dependent centrosome inactivation in Drosophila embryos. Nature Cell Biol. 2, 90–95 (2000).Loss of microtubule nucleation and γ-tubulin from centrosomes after DNA damage.

    CAS  PubMed  Article  Google Scholar 

  97. 97

    Hinchcliffe, E. H. & Sluder, G. 'It takes two to tango': understanding how centrosome duplication is regulated throughout the cell cycle. Genes Dev. 15, 1167–1181 (2001).

    CAS  PubMed  Article  Google Scholar 

  98. 98

    Lange, B. M. & Gull, K. A molecular marker for centriole maturation in the mammalian cell cycle. J. Cell Biol. 130, 919–927 (1995).

    CAS  PubMed  Article  Google Scholar 

  99. 99

    Chang, P. & Stearns, T. δ-tubulin and ɛ-tubulin: two new human centrosomal tubulins reveal new aspects of centrosome structure and function. Nature Cell Biol. 2, 30–35 (2000).Identification of two novel centrosome-associated tubulins in humans, δ and ɛ.

    CAS  PubMed  Article  Google Scholar 

  100. 100

    Paoletti, A., Moudjou, M., Paintrand, M., Salisbury, J. L. & Bornens, M. Most of centrin in animal cells is not centrosome-associated and centrosomal centrin is confined to the distal lumen of centrioles. J. Cell Sci. 109, 3089–3102 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Ruiz, F., Beisson, J., Rossier, J. & Dupuis-Williams, P. Basal body duplication in Paramecium requires γ-tubulin. Curr. Biol. 9, 43–46 (1999).

    CAS  PubMed  Article  Google Scholar 

  102. 102

    Palazzo, R. E., Vaisberg, E., Cole, R. W. & Rieder, C. L. Centriole duplication in lysates of Spisula solidissima oocytes. Science 256, 219–221 (1992).

    CAS  PubMed  Article  Google Scholar 

  103. 103

    Marshall, W. F., Vucica, Y. & Rosenbaum, J. L. Kinetics and regulation of de novo centriole assembly. Implications for the mechanism of centriole duplication. Curr. Biol. 11, 308–317 (2001).Demonstration of centriole/basal body formation de novo in Spisula and Chlamydomonas.

    CAS  PubMed  Article  Google Scholar 

  104. 104

    Andersen, S. S. Molecular characteristics of the centrosome. Int. Rev. Cytol. 187, 51–109 (1999).

    CAS  PubMed  Article  Google Scholar 

  105. 105

    Fry, A. M., Meraldi, P. & Nigg, E. A. A centrosomal function for the human Nek2 protein kinase, a member of the NIMA family of cell cycle regulators. EMBO J. 17, 470–481 (1998).Identification of a kinase that seems to be involved in centrosome splitting in G2/M.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106

    Mayor, T., Stierhof, Y. D., Tanaka, K., Fry, A. M. & Nigg, E. A. The centrosomal protein C-Nap1 is required for cell cycle-regulated centrosome cohesion. J. Cell Biol. 151, 837–846 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107

    Sharp, D. J., Rogers, G. C. & Scholey, J. M. Microtubule motors in mitosis. Nature 407, 41–47 (2000).

    CAS  PubMed  Article  Google Scholar 

  108. 108

    Matsumoto, Y., Hayashi, K. & Nishida, E. Cyclin-dependent kinase 2 (Cdk2) is required for centrosome duplication in mammalian cells. Curr. Biol. 9, 429–432 (1999).

    CAS  PubMed  Article  Google Scholar 

  109. 109

    Meraldi, P., Lukas, J., Fry, A. M., Bartek, J. & Nigg, E. A. Centrosome duplication in mammalian somatic cells requires E2F and Cdk2–cyclin A. Nature Cell Biol. 1, 88–93 (1999).References 108 and 109 describe the identification of Cdk2–cyclinE/A as regulators of centrosome duplication in mammalian cells.

    CAS  PubMed  Article  Google Scholar 

  110. 110

    Fisk, H. A. & Winey, M. The mouse Mps1p-like kinase regulates centrosome duplication. Cell 106, 95–104 (2001).

    CAS  Article  PubMed  Google Scholar 

  111. 111

    Okuda, M. et al. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 103, 127–140 (2000).

    CAS  Article  PubMed  Google Scholar 

  112. 112

    Tokuyama, Y., Horn, H. F., Kawamura, K., Tarapore, P. & Fukasawa, K. Specific phosphorylation of nucleophosmin on Thr199 by cyclin-dependent kinase 2-cyclin E and its role in centrosome duplication. J. Biol. Chem. 276, 21529–21537 (2001).

    CAS  PubMed  Article  Google Scholar 

  113. 113

    Tarapore, P., Horn, H. F., Tokuyama, Y. & Fukasawa, K. Direct regulation of the centrosome duplication cycle by the p53-p21(Waf1/Cip1) pathway. Oncogene 20, 3173–3184 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114

    Freed, E. et al. Components of an SFC ubiquitin ligase localize to centrosomes and regulate the centrosome duplication cycle. Genes Dev. 13, 2242–2257 (1999).Demonstrates a role for the ubiquitin-mediated degradation pathway in centrosome duplication.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115

    Nakayama, K. et al. Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication. EMBO J. 19, 2069–2081 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116

    Wojcik, E. J., Glover, D. M. & Hays, T. S. The SCF ubiquitin ligase protein slimb regulates centrosome duplication in Drosophila. Curr. Biol. 10, 1131–1134 (2000).

    CAS  PubMed  Article  Google Scholar 

  117. 117

    O'Connell, K. F. et al. The C. elegans zyg-1 gene encodes a regulator of centrosome duplication with distinct maternal and paternal roles in the embryo. Cell 105, 547–558 (2001).

    CAS  PubMed  Article  Google Scholar 

  118. 118

    Wakefield, J. G., Huang, J. Y. & Raff, J. W. Centrosomes have a role in regulating the destruction of cyclin B in early Drosophila embryos. Curr. Biol. 10, 1367–1370 (2000).

    CAS  PubMed  Article  Google Scholar 

  119. 119

    Clute, P. & Pines, J. Temporal and spatial control of cyclin B1 destruction in metaphase. Nature Cell Biol. 1, 82–87 (1999).References 118 and 119 demonstrate that cyclin degradation is spatially regulated, beginning on centrosomes/spindle poles and moving up the spindle to the chromosomes.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120

    Diviani, D. & Scott, J. D. AKAP signaling complexes at the cytoskeleton. J. Cell Sci. 114, 1431–1437 (2001).

    CAS  PubMed  Google Scholar 

  121. 121

    Feliciello, A., Gottesman, M. E. & Avvedimento, E. V. The biological functions of A-kinase anchor proteins. J. Mol. Biol. 308, 99–114 (2001).

    CAS  PubMed  Article  Google Scholar 

  122. 122

    Groisman, I. et al. CPEB, maskin, and cyclin B1 mRNA at the mitotic apparatus: implications for local translational control of cell division. Cell 103, 435–447 (2000).

    CAS  Article  PubMed  Google Scholar 

  123. 123

    Brinkley, B. R. & Goepfert, T. M. Supernumerary centrosomes and cancer: Boveri's hypothesis resurrected. Cell Motil. Cytoskel. 41, 281–288 (1998).

    CAS  Article  Google Scholar 

  124. 124

    Marx, J. Cell biology. Do centrosome abnormalities lead to cancer? Science 292, 426–429 (2001).

    CAS  PubMed  Article  Google Scholar 

  125. 125

    Pihan, G. A. et al. Centrosome defects can account for cellular and genetic changes that characterize prostate cancer progression. Cancer Res. 61, 2212–2219 (2001).

    CAS  PubMed  Google Scholar 

  126. 126

    Rosenbaum, J. L., Cole, D. G. & Diener, D. R. Intraflagellar transport: the eyes have it. J. Cell Biol. 144, 385–388 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127

    Quintyne, N. J. et al. Dynactin is required for microtubule anchoring at centrosomes. J. Cell Biol. 147, 1–14 (1999).

    Article  Google Scholar 

  128. 128

    Pihan, G. A. et al. Centrosome defects and genetic instability in malignant tumors. Cancer Res. 58, 3974–3985 (1998).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I apologize to colleagues whose work is not discussed or cited owing to space constraints. I would like to thank K. Sluder, B. Theurkauf, F. McNally and D. McCollum for critical reading of the manuscript. S.D. is an American Heart Established Investigator and is supported by the National Institutes of Health, the National Cancer Institute and the Department of Defense.

Author information

Affiliations

Authors

Related links

Related links

DATABASE LINKS

γ-tubulin

α-tubulin

β-tubulin

Spc97

Spc98

Tub4

Spc72

Spc110

Asp

GCP2

GCP3

pericentrin

pericentrin B

polo

aurora

ninein

katanin

XKCM1

XKIF2

cytoplasmic dynein

centrin

Tem1

Lte1

ɛ-tubulin

NEK2

cNAP1

Cdk2

cyclin E

cyclin A

Mps1

nucleophosmin

p53

p21

ZYG-1

cyclin B

FURTHER INFORMATION

movie of pericentrin

movie of PCM-1

Glossary

INTERPHASE

The period between two mitotic divisions.

CENTRIOLES

Open-ended cylinders, comprised of nine sets of triplet microtubules linked together and containing appendages on the outside and protein assemblies and sometimes vesicles on the inside. Centrosomes usually contain two centrioles.

MICROTUBULE

A hollow tube, 25 nm in diameter, formed by the lateral association of 13 protofilaments, which are themselves polymers of α- and β-tubulin subunits.

SPINDLE POLE BODY

The acentriolar microtubule-organizing centre of yeast and diatoms. It is a plaque-like structure that is embedded in the nuclear membrane that faces the cytoplasm on one side and the nuclear interior on the other.

COILED COIL

A protein domain that forms a bundle of two or three α-helices. Whereas short coiled-coil domains are involved in protein interactions, long coiled-coil domains forming long rods occur in structural or motor proteins.

PRIMARY CILIUM

A single, probably non-motile, cilium that grows from the maternal centriole of the centrosome in most cell types.

CYTOKINESIS

The process of cytoplasmic division.

MITOSIS

The process of nuclear division.

ASTER

A radial array of microtubules focused on and usually nucleated by centrosomes or aggregates of centrosome/spinlde pole proteins.

S VALUE

(Sedimentation coefficient.) A standardized value, describing migration of molecules/particles under a centrifugal force.

KINETOCHORE

A structure that connects each chromatid to the spindle microtubules, which shorten as pairs of chromatids are separated to opposite poles.

ANEUPLOIDY

Presence of extra copies, or no copies, of some chromosomes.

CHECKPOINT

A point where the cell division cycle can be halted until conditions are suitable for the cell to proceed to the next stage.

GUANINE-NUCLEOTIDE EXCHANGE FACTOR

A protein that facilitates the exchange of GDP (guanine diphosphate) for GTP (guanine triphosphate) in the nucleotide-binding pocket of a GTP-binding protein.

ORTHOLOGUE

Homologous genes in different species, the lineages of which derive from a common ancestral gene without gene duplication or horizontal transmission.

SCF COMPLEX

A multisubunit ubiquitin ligase that contains Skp1, a member of the cullin family (Cul1), and an F-box-containing protein (Skp2), as well as a RING-finger-containing protein (Roc1/Rbx1).

PROTEASOME

Large multisubunit protease complex that selectively degrades intracellular proteins. Targeting to proteasomes most often occurs through attachment of multi-ubiquitin tags.

MALD TOF

A method designed to determine peptide mass maps of very small amounts of enzymatically digested proteins with a very high degree of accuracy. Masses are determined by measuring peptides that are ionized in a vacuum.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Doxsey, S. Re-evaluating centrosome function. Nat Rev Mol Cell Biol 2, 688–698 (2001). https://doi.org/10.1038/35089575

Download citation

Further reading