Two for two: Cdk2 and its role in centrosome doubling

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 cell 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 spinle 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 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 may 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.