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Two for two: Cdk2 and its role in centrosome doubling

Oncogene volume 21, pages 6154–6160 (2002)Cite this article

The magic number in cell division is two: during S phase the cell makes two copies of its genome, and during mitosis the equal segregation of all sister chromosomes to the two daughter cells critically depends upon the formation of a bipolar mitotic spindle. Since spindle polarity in higher animal cells is usually dependent upon the number of centrosomes present, the cell must have exactly two centrosomes by the onset of mitosis or else mitotic defects will occur that can have disastrous consequences for the organism (reviewed in Brinkley, 2001; Rieder et al., 2001). For example, failure of the interphase centrosome to duplicate before mitosis leads to a monopolar spindle and the formation of a single polyploid daughter cell. Conversely, if a cell contains more than the normal two centrosomes, it is apt to assemble a multipolar spindle at mitosis, which randomly distributes chromosomes to multiple daughter cells. Finally, a complete lack of a centrosome does not prevent the formation of a bipolar spindle (Khodjakov et al., 2000), but does lead to an increased incidence of cleavage failure (Hinchcliffe et al., 2001; Khodjakov and Rieder, 2001; Piel et al., 2001). Thus, mis-regulation of centrosome number produces genetic imbalances that can contribute to the loss of growth regulation and the genesis of the transformed phenotype. Indeed, the multiple centrosomes found in the cells of many high-grade human tumors are thought to cause the genomic instability that allows the evolution of aggressive growth characteristics (Lingle and Salisbury, 2000). Thus, it is of obvious importance for the cell to exercise tight control over centrosome duplication. In this review we discuss the development of our understanding of how Cdk2 – cyclin E participates in the control of centrosome duplication.

At the end of mitosis each daughter cell inherits a single centrosome and by the start of the next mitosis each contains just two centrosomes that will establish the bipolar spindle. This precise doubling of the interphase centrosome is known as centrosome duplication or centrosome reproduction (see Hinchcliffe and Sluder, 2001; Stearns, 2001). In mammalian cells this process is thought to begin in late G1 with the loss of the orthogonal relationship between the mother and daughter centrioles (Kuriyama and Borisy, 1981; however, see Mack and Rattner, 1993; Piel et al., 2000, 2001 for examples of centriole separation earlier in the cell cycle). Centriole duplication starts at the beginning of S phase or during S phase with the appearance of short daughter centrioles, or procentrioles, at right angles to the two original centrioles. These procentrioles elongate during S and G2, reaching mature length in mitosis or the following G1 (Kuriyama and Borisy, 1981; Lange et al., 2000). The completion of centrosome reproduction occurs with daughter centrosome disjunction and separation at a variable time in G2, with pairs of mother–daughter centrioles in each centrosome (Aubin et al., 1980; Kochanski and Borisy, 1990; Sharp et al., 2000).

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Acknowledgements

We thank Mark Winey, Michel Bornens, Tim Stearns, Peter Jackson, Jim Maller, Conly Rieder and Alexey Khodjakov for their continued conversations on cell cycle regulation of centrosome reproduction and function. Thanks also to Kenji Fukasawa for editorial input and patience. Work from the Sluder Laboratory is funded by a grant from the National Institutes of Health (GM 30758). EH Hinchcliffe is supported by funds from the Walther Institute for Cancer Research, and the University of Notre Dame.

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  1. Department of Biological Sciences, and the Walther Cancer Research Institute, University of Notre Dame, Notre Dame, 46556, Indiana, IN, USA

    Edward H Hinchcliffe

  2. Department of Cell Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, 01605, Massachusetts, MA, USA

    Greenfield Sluder

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Correspondence to Greenfield Sluder.

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Hinchcliffe, E., Sluder, G. Two for two: Cdk2 and its role in centrosome doubling. Oncogene 21, 6154–6160 (2002). https://doi.org/10.1038/sj.onc.1205826

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