Deregulated cyclin E induces chromosome instability.
Cyclin E, a regulatory subunit of cyclin-dependent kinase 2 (Cdk2), is an important regulator of entry into S phase in the mammalian cell cycle. In normal dividing cells, cyclin E accumulates at the G1/S-phase boundary and is degraded as cells progress through S phase. However, in many human tumours cyclin E is overexpressed and the levels of protein and kinase activity are often deregulated relative to the cell cycle. It is not understood how alterations in expression of cyclin E contribute to tumorigenesis. Here we show that constitutive cyclin-E overexpression in both immortalized rat embryo fibroblasts and human breast epithelial cells results in chromosome instability (CIN). In contrast, analogous expression of cyclin D1 or A does not increase the frequency of CIN. Cyclin-E-expressing cells that exhibit CIN have normal centrosome numbers. However, constitutive overexpression of cyclin E impairs S-phase progression, indicating that aberrant regulation of this process may be responsible for the CIN observed. These results indicate that downregulation of cyclin-E/Cdk2 kinase activity following the G1/S-phase transition may be necessary for the maintenance of karyotypic stability.
Spruck
C H
CH
Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Won
K A
KA
Reed
S I
SI
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D042846:CDC2-CDC28 Kinases; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002869:Chromosome Aberrations; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D006801:Humans; D007621:Karyotyping; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D016196:S Phase; D014407:Tumor Cells, Cultured
D019927:Cyclin E; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases