Deregulated cyclin E induces chromosome instability

Cyclin E, a regulatory subunit of cyclin-dependent kinase 2 (Cdk2), is an i mportant regulator of entry into S phase in the mammalian cell cycle. In no rmal dividing cells, cyclin E accumulates at the G(1)/S-phase boundary and is degraded as cells progress through S phase(1,2). However, in many human tumours cyclin E is overexpressed(3) and the levels of protein and kinase a ctivity are often deregulated relative to the cell cycle(4-7). It is not un derstood how alterations in expression of cyclin E contribute to tumorigene sis. Here we show that constitutive cyclin-E overexpression in both immorta lized rat embryo fibroblasts and human breast epithelial cells results in c hromosome instability (CIN). In contrast, analogous expression of cyclin D1 or A does not increase the frequency of GIN. Cyclin-E-expressing cells tha t exhibit CIN have normal centrosome numbers. However, constitutive overexp ression of cyclin E impairs S-phase progression, indicating that aberrant r egulation of this process may be responsible for the CIN observed. These re sults indicate that downregulation of cyclin-E/Cdk2 kinase activity followi ng the G(1)/S-phase transition may be necessary for the maintenance of kary otypic stability.